Psychosomatic Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McCaffery, J. M.
Right arrow Articles by Lespérance, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McCaffery, J. M.
Right arrow Articles by Lespérance, F.
Related Collections
Right arrow Genetics
Right arrow Reviews
Right arrow Coronary Artery Disease
Psychosomatic Medicine 68:187-200 (2006)
© 2006 American Psychosomatic Society

REVIEWS

Common Genetic Vulnerability to Depressive Symptoms and Coronary Artery Disease: A Review and Development of Candidate Genes Related to Inflammation and Serotonin

Jeanne M. McCaffery, PhD, Nancy Frasure-Smith, PhD, Marie-Pierre Dubé, PhD, Pierre Théroux, MD, Guy A. Rouleau, MD, PhD, QingLing Duan, BSc and Francois Lespérance, MD

From the Weight Control and Diabetes Research Center (J.M.M.), Brown Medical School and the Miriam Hospital; Department of Psychiatry and School of Nursing (N.F.-S.), McGill University; the Research Center, Montreal Heart Institute; the Department of Psychiatry University of Montreal; and the Research Center, Centre Hospitalier de l'Université de Montréal; Department of Medicine (M.-P.D.), Université de Montréal and the Research Centre, Montreal Heart Institute; Montreal Heart Institute (P.T.) and the University of Montreal; Department of Medicine (G.A.R.), University of Montreal and the Research Center, Centre Hospitalier de l'Université de Montréal; Department of Human Genetics (Q.L.D.), McGill University; and Department of Psychiatry (F.L.), Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Jeanne M. McCaffery, PhD, Weight Control and Diabetes Research Center, 196 Richmond Street, Providence, RI 02903. E-mail: Jeanne_McCaffery{at}brown.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUMMARY AND INTEGRATION
 NOTES
 REFERENCES
 
Objective: Although it is well established that depressive symptoms are associated with recurrent cardiac events among cardiac patients and novel cardiac events among participants with no known coronary artery disease (CAD), the nature of this association remains unclear. In this regard, little attention has been paid to the possibility that common genetic vulnerability contributes to both depressive symptoms and CAD. In this paper, we review the existing evidence for common genetic contributions to depression and CAD, primarily using evidence from twin and family studies, followed by a review of two major pathophysiological mechanisms thought to underlie covariation between depressive symptoms and CAD: inflammation and serotonin. We conclude with an overview of select candidate genes within these pathways.

Methods: Literature review.

Results: In twin studies, both depression and CAD appear heritable. In the only twin study to consider depression and CAD jointly, the correlation across heritabilities was 0.42, suggesting that nearly 20% of variability in depressive symptoms and CAD was attributable to common genetic factors. In addition, although it is plausible that genetic variation related to inflammation and serotonin may be associated with both depression and CAD, genetic variation related to inflammation has been primary examined in relation to CAD, whereas genetic variation in the serotonin system has been primarily examined in relation to depression.

Conclusions: It appears that the covariation of depressive symptoms and CAD may be attributable, in part, to a common genetic vulnerability. Although several pathways may be involved, genes within the inflammation and serotonin pathways may serve as good candidates for the first steps in identifying genetic variation important for depression, CAD or both.

Key Words: coronary artery disease • depression • genetics • twins

Abbreviations: CAD = coronary artery disease; MI = myocardial infarction; MZ = monozygotic; DZ = dizygotic; CES-D = Centers for Epidemiological Studies–Depression Scale; BDI = Beck Depression Inventory; VET = Vietnam-Era Twin; LOD = log10 of odds ratio; CSF 5-HIAA = 5-hydroxyindoleatic acid in cerebrospinal fluid; CYP2A6 = cytochrome P450, subfamily IIA, polypeptide 6 gene; CHRB2 = beta2 nicotine receptor subunit gene; DRD4 = dopamine D4 receptor gene; AVP1B = arginine vasopressin receptor 1b gene; FACL4 = long-chain fatty acid-CoA ligase Type 4 gene; MEF2A = myocyte-enhancing factor 2A; IL-6 = interleukin 6; TNF-{alpha} = tumor necrosis factor-{alpha}; ICAM-1 = intercellular adhesion molecule-1; CRP = c-reactive protein; IL-1ß = interleukin 1ß; V-CAM-1 = vascular adhesion molecule 1; 5-HT = serotonin; TPH = tryptophan hydroxylase; 5-HTT = serotonin transporter; MPO = myeloperoxydase; A = adenine nucleic acid; C = cytosine nucleic acid; G = guanine nucleic acid; T = thymine nucleic acid; mRNA = messenger ribonucleic acid; IL-1B, TNFA, MPO, IL-6, ICAM-1, VCAM-1, 5-HTT, 5-HT2A, 5-HT2B, TPH1, TPH2 = genes coding for these proteins, respectively, s allele "short," or deletion, allele at the common variation in 5-HTT, l allele "long," or insertion, allele at the common variation in 5-HTT; SELE = E-selectin gene; SELP = P-selectin gene.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUMMARY AND INTEGRATION
 NOTES
 REFERENCES
 
It is well established that depressive symptoms predict CAD both in community samples with no known CAD (1–7) and among patients who have already experienced a clinical event (5,8–18). Nonetheless, the direction of association remains unclear. It has been hypothesized that depressive symptoms predispose to CAD through altered neuroendocrine function (dysregulated hypothalamic-pituitary-adrenal cortical function or autonomic function), inflammation, platelet activation, health behaviors, or side effects of pharmacological treatment of depression (19). It is also possible that CAD causes depressive symptoms perhaps due to cardiac-related disability, the stress of a poor prognosis, or neurological effects of disease processes, such as chronic inflammation or underlying microvascular disease (19,20). Although given much less consideration, it is also plausible that third factors, such as a common genetic vulnerability, account for the observed association between depression and CAD. For example, genetic variants within key elements of pathways thought to underlie the covariation of depression and CAD may contribute to the co-occurrence of depression and CAD in a given individual (21). In this paper, we review the existing evidence for a genetic contribution to depression and CAD, primarily using evidence from twin and family studies, followed by a review of two major pathophysiological mechanisms thought to underlie covariation between depressive symptoms and CAD: inflammation and serotonin. We conclude with an overview of select candidate genes within these pathways.

Twin and Family Studies of Depression and CAD
For several decades, it has been known that CAD tends to run in families (22–26). Twin studies have further established that this observed familial aggregation appears more attributable to genetic than environmental factors. For example, among 21,004 Swedish twins followed for 26 years, the relative hazard of death from CAD when one's twin died before the age of 55 years was 8.1 among male monozygotic (MZ) twins as compared with 3.8 among male dizygotic (DZ) twins (27). Among women, the relative hazard was 15.0 when a MZ twin died from CAD before age 65 relative to 2.6 for DZ co-twins. Heritability estimates at 36-year follow-up in this sample were 0.57 and 0.38 among males and females, respectively, although differences among MZ and DZ twin pairs appeared to diminish over time (28).

A recent review and meta analysis of twin and family studies indicate that major depression is also more common among close relatives of individuals who have been depressed (29). Across five studies, first-degree relatives of a depressed proband experienced a 2.84 times greater risk of depression than relatives of nondepressed probands. In a meta analysis, including more than 21,000 twins (29), the heritability of major depression was 0.37, with the remainder of variance attributable to unique (individual) effects, indicating that observed familial transmission of depression is largely attributable to genetic factors. Self-reports of depressive symptoms, using questionnaire measures, such as the CES-D or BDI, also show a modest but significant genetic influence (30–32).

Despite evidence that both depressive symptoms and CAD each run in families and are heritable, only one study has examined whether common genetic effects may underlie vulnerability to both. Scherrer and colleagues (33) estimated genetic and environmental contributions to the covariation of depressive symptoms and CAD in a sample of 2,731 male-male twin pairs from the Vietnam-Era Twin (VET) Registry. Consistent with other research showing an association between depressive symptoms and CAD, self-reports of physician diagnosed hypertension and a composite measure of CAD (angina + myocardial infarction + coronary heart disease + bypass + angioplasty) were each more common among individuals reporting five or more symptoms of depression and a greater severity of depression. Univariate twin modeling indicated that depressive symptoms, hypertension, and heart disease were each significantly heritable with no influence of shared environmental factors. Similarly, in bivariate modeling, the associations between depressive symptoms and both hypertension and heart disease were attributable solely to genetic effects. Indeed, the correlation between genetic influences on depression and on the composite measure of heart disease was 0.42, suggesting that nearly 20% of genetic influences on each were common across depression and heart disease in the VET sample. Taken together with the previous reports of heritability of depressive symptoms and CAD individually, this study of covariation strongly suggests common genetic influences across depression and CAD.

Genetic Linkage
Within families, it is possible to examine the extent to which a trait co-segregates with genetic markers at tested chromosomal segments. The most commonly used statistic for model-based linkage analysis is the maximum likelihood ratio. This tests the hypothesis of disease and marker co-segregation versus the null hypothesis of random segregation. For historical reasons of convenience, the base 10 logarithm of the ratio of the likelihoods is used and referred to as the LOD score (log of odds) (34). The conventional significance threshold used in linkage analysis is LOD ≥ 3 for Mendelian diseases. The genomewide significance threshold is generally set slightly higher to LOD = 3.3 (35). A candidate location interval for the position of the searched gene is usually derived by marking the position on the genetic map where the curve reaches the maximum LOD-1 points, or more conservatively, the LOD-2 points. With this approach, it is possible to compare the results of linkage studies to find overlapping intervals. In the study of more complex phenotypes such as depression and CVD, replication of linkage findings in independent studies is a valuable means of prioritizing findings.

In a recent review of linkage studies of depression, together with linkage results pertaining to anxiety and neuroticism, Huezo-Diaz and colleagues (36) concluded that, although there is some overlap of linkage intervals between studies, for example, on chromosomes 1, 4, 6, 7, 8, 11, and 12, replication of findings is sometimes ambiguous because of the large intermarker distances and interstudy marker differences. Linkage intervals specific to major depression include: 2q33 to 35 in females (37,38),12q22 to 23.3 (39), and 15q25.3 to 26.2 (40). Hamet and Tremblay (41) note that the linkage peak 12p22 to 23.3 is consistent with a linkage investigation of neuroticism (42) in the region of TPH2, a gene that codes for tryptophan hydroxylase, the rate-limiting step in the production of serotonin (43). 5-HT2B is in the region of the 2q signals (38).

Genome-wide approaches to CAD were recently reviewed by Wang (44). Genome-wide linkage studies have resulted in the identification of novel loci that influence risk for MI, CAD, and acute coronary syndrome, specifically 1p34 to 36, 2q21.1 to 22, 2q36 to 37, 3q13, 6p21, 13q12 to 13, 14q, 15q26, 16p13, 22q13.1, and Xq23 to 26. Follow-up of these results has produced several positional candidate genes, which have, in turn, been associated with disease outcomes. For example, the 15q26 linkage peak led to the discovery of a 21 base pair exonic deletion in MEF2A associated with an autosomal dominant form of CAD (45). Three additional variants within the same gene were associated with less severe forms of CAD (46). MEF2A codes for a transcription factor in the endothelium potentially triggering inflammation.

Although not an analysis of depression and CAD comorbdity per se, overlap of depression and CAD linkage signals may suggest the potential for common candidate genes that contribute to both depression and CAD. Given the lack of replication within phenotype, particularly depression, this approach is somewhat premature. Nonetheless, individual studies of depression and CAD have both found signals in the regions of 2q33 to 35 and 15q25.3 to 26.2. Candidate genes related to serotonin or inflammation in these regions include 5-HT2B (38) and MEF2A (45).

The reliability of genome-wide studies for the identification of complex disease genes has been subjected to some criticism in the past years. There are concerns that the lower gene effects in such diseases resulting in attenuated familial aggregation, as well as the heterogeneity in the familial etiologies, may impede power to detect true candidates by linkage analysis (47). As such, studies relying on case-control association tests with candidate genes are increasingly used as a valid alternative.

Potential Pathways Underlying Depression and Heart Disease
Genetic variation contributing to risk of depression and CAD may also be identified in candidate genes within biological pathways thought to contribute to both. Recent reviews (20,48–50) have argued that links between depression and CAD may be due to an association of depression with other cardiovascular risk factors (e.g., smoking, reduced exercise, hypertension, diabetes), greater coronary disease severity, differential adherence to medical treatments, antidepressant cardiotoxicity, or deficits in eicosapentaenoic acid levels in the omega-3 fatty acid pathway. There is also evidence of depression-related changes in platelet reactivity, inflammatory processes, and hypothalamic-pituitary-adrenal cortical and autonomic regulation that may also contribute to the observed association between depression and CAD. Nearly all of these pathways may be influenced by individual differences in genetic vulnerability, which in turn could influence the expression of depression and CAD. For example, cigarette smoking is well known to increase risk for both CAD and depressive symptoms. Initial investigations of candidate genes indicate that variation in genes related to nicotine metabolism (e.g., CYP2A6), nicotinic receptor activation (e.g., CHRB2), and dopamine neurotransmission (e.g., DRD4) may increase risk for smoking initiation and difficulty quitting (51). There is also evidence that genes that code for key elements in the sympathetic nervous system (52–54) and hypothalamic-pituitary adrenal cortical axis (55,56) contribute to psychophysiological responses to stress, whereas genes within the parasympathetic nervous system have been related to heart rate variability (57). In terms of direct associations with depression phenotypes, polymorphisms within FKBP5, a glucocorticoid receptor-regulating cochaperone, have been associated with HPA axis response in depression and recurrence of depressive episodes (58). In a second study, a block of SNPs (haplotype) within the gene coding for arginine vasopressin receptor 1b (AVP1B), involved in adrenocorticotrophic hormone (ACTH) release, also predicted major depression (59). Long-chain fatty acid co-A ligase 4 (FACL4), a key enzyme required for the incorporation of omega-3 and -6 fatty acids into phospholipid membranes, has also been associated with major depression (60). Although genes contributing to the above pathways, or other pathways that we are not yet aware of may contribute to the covariation of depression and CAD. This review focuses on two candidate pathways as an illustration, the inflammation and serotonin pathways.

Inflammation
Inflammation is now thought to be involved in all stages of atherosclerosis, ranging from a role in initial recruitment of leukocytes to injured endothelium to a role in rendering a fibrous cap weak and susceptible to rupture at an advanced atherosclerotic plaque site (61,62). Indeed, chronic low-grade inflammation, as indexed by elevated inflammatory markers, has been shown to predict the development of cardiovascular events among persons with no known CAD. For example, proinflammatory cytokines, including IL-6 (63,64) and TNF-{alpha} (65), cellular adhesion molecules, such as ICAM-1 (66,67), and acute phase reactants, including CRP (63,68–73), have each been shown to increase risk for CAD in prospective epidemiological investigations among initially healthy participants. In addition, across various studies, IL-1ß (74–76), V-CAM-1 (77), and P-selectin (77,78) have each been shown to be elevated among CAD patients as compared with controls. IL-6 (79), CRP (80), ICAM-1 (81,82), VCAM-1 (82), and E-selectin (82) also appear to predict poor prognosis among patients with established CAD.

Several of the inflammatory markers that increase risk for CAD have also been associated with depression. Perhaps the most support to date has been shown for an elevation of IL-6 associated with depressive symptomology (83–88), an effect that appears to remit with treatment of the depression (89). As IL-6 stimulates release of CRP, it is not surprising that elevations in CRP are also seen among depressed but otherwise healthy participants (83,90). Lespérance and colleagues found significant increases in CRP among depressed cardiac patients, but only among those not treated with statins (a class of lipid-lowering medications known to reduce CRP levels) (91). Elevated sICAM-1 levels were seen among depressed relative to nondepressed cardiac patients in the same sample (92) and have also been observed in healthy young adults with major depression (93). Furthermore, in animal models, IL-6, IL-1b, and TNF-{alpha} have each been implicated in behavioral depression associated with sickness behavior (94,95).

Overall, it is clear that aspects of the chronic inflammation associated with CAD appear to accompany depression. As inflammation may contribute to the development of CAD and depression (85), it is possible that genetic variation related to inflammation could influence both.

Serotonin
The monoamine hypothesis of depression has evolved over the past 20 years and has contributed to important advances in the pharmacologic treatment for depression (96). Although it had been hypothesized that serotonin deficiency specifically contributes to depression, efforts to correlate depression with indices of central serotonin have been inconclusive. It is now thought that the interaction of low brain serotonin levels with other neurotransmitter systems, including dopamine, norepinephrine, glutamate, and GABA, as well as the associated signaling proteins, may be important in the pathophysiology of depression (96).

Serotonin may contribute to CAD through central and peripheral mechanisms. CNS 5-HT has been associated with psychological characteristics associated with cardiovascular disease, including depression. In addition, it has been shown that central serotonin pathways innervate brain regions involved in sympathetic effects on cardiovascular function. Two major serotonin receptor subtypes, 5-HT1A and 5-HT2A, mediate the effects of sympathetic activity on cardiovascular function, the former causing sympathoinhibition and the latter sympathoexcitation in rat models (24). A "knockout" mouse model targeting a third receptor, the serotonin transporter (5-HTT), has also been developed (25). These "knockout" mice show nearly a fourfold greater increase in adrenocorticotropic hormone in response to the stress of injection than controls (28).

In the periphery, serotonin induces platelet aggregation and, among those with existing endothelial dysfunction, vasoconstriction (97). The effects of 5-HT on platelet aggregation and vasoconstriction are mediated by 5-HT2A receptors (98) and reuptake of circulating 5-HT into platelets is achieved via the 5-HT transporter (5-HTT). 5-HT also promotes smooth muscle cell proliferation in aortic tissue, an effect that is abolished by 5-HT2A receptor antagonists (99). It has also been shown that the 5-HT2B receptor is essential for sympathetic-induced cardiac hypertrophy in animal models (100,101).

Historically, platelets were used as peripheral models of central serotonin nerve terminals and thus have been studied extensively in depression (102). Several investigations have shown increased platelet 5-HT2A binding density among depressed patients (102–104). In addition, depressed patients exhibit reduced platelet and brain serotonin transporter sites as detected by [3H]imipramine hydrochloride (105–109) and [3H]paroxetine hydrochloride (108,110) binding. The increased 5-HT2A receptor binding density, together with fewer 5-HTT sites, suggests that depressed patients may be particularly vulnerable to platelet aggregation and vasoconstriction associated with CAD (48). Consistent with this hypothesis, one small study suggested that depressed patients show enhanced baseline platelet activation and responsiveness to orthostatic challenge as compared with healthy controls (111), while a second study indicated that depressed cardiac patients exhibit increased platelet activation, as indexed by plasma platelet factor 4 and ß-thromboglobulin, compared with nondepressed controls with CVD and healthy controls (112). Treatment of depression with sertraline has also been shown to diminish the heightened release of ß- thromoboglobulin seen among depressed patients as compared with placebo (113).

Candidate Genes Within Inflammation and Serotonin Pathways
In the next section, we highlight key genes related to inflammation and serotonin function that exhibit genetic associations with either depression or CAD. A list of these candidate genes for depression and CAD comorbidity is provided in Table 1.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Select Candidate Genes for Depression and CAD Comorbidity Within the Inflammation and Serotonin-Mediated Platelet Aggregation Pathways

 

Inflammation
Several genes within the inflammation pathway have been examined in relation to cardiovascular disease. In the vast majority of cases, investigations have relied on a single variant within the gene. To the extent that the variant identified has functional significance for the structure or rate of transcription of the protein, which in turn influences the phenotype of interest, association with the single variant may be a good approach. However, a single variant provides sparse information about variation throughout the gene, potentially contributing to inconsistent results (114). To date, few inflammation genes related to cardiovascular disease have been examined in relation to depression. Existing studies are reviewed below, beginning with the inflammation genes that have been studied in relation to depression (IL-1B, TNFA), followed by genes of interest that, to our knowledge, have not yet been investigated in relation to depression (MEF2A, MPO, IL-6, ICAM-1, VCAM-1, SELE, SELP).

IL-1B
A role for variability in the IL-1B gene as a predictor of cardiovascular disease is suggested by animal models in which the IL-1B gene is deleted (in "knockout" mouse models). In an apolipoprotein E deficient mouse model, the additional knockout of the IL-1B gene resulted in a 30% reduction in atherosclerotic lesions as compared with animals expressing IL-1B (115). In humans, a C to T substitution at position –511 in the promoter region has been reported. Although this locus was associated with blood pressure in a sample of hypertensive Chinese (116), it did not differ among patients with angiographically documented CAD as compared with controls in a second study (117). A small literature now suggests that the C allele at position –511 may predict depression-related phenotypes. For example, the C allele was more prevalent among patients with dysthymia as compared with controls in one study (118) and was associated with severity of depressive symptoms and treatment response to fluoxetine, although not major depression per se, in a second (119). Nonetheless, in a third investigation involving patients with Alzheimer's and controls, the T allele was predictive of depressive symptoms (120).

TNFA
Tumor necrosis factor-{alpha} is a pro-inflammatory cytokine contributing to atherosclerotic plaque formation. Although early review indicated an inconsistent relationship with CAD (121), a G to A substitution at position –308 in the promoter region has now been associated with enhanced TNF-{alpha} production (122), enhanced inflammatory response after cardiac surgery (123), insulin resistance (124,125), CAD among Type II diabetics (126), and elevated CRP among participants with vital exhaustion, as defined by undue fatigue, difficulty sleeping, general malaise, apathy, irritability, and loss of energy (127). In addition, one study has suggested that variability at the –308 position may influence depressive symptoms. In a similar direction as studies showing enhanced inflammatory effects, the A allele has been shown to be more prevalent among patients with major depression than controls (128).

MEF2A
MEF2A, coding for a transcription factor in the endothelium potentially associated with increased susceptibility to inflammation, contains a 21-base pair exonic deletion associated with an autosomal dominant form of CAD (45). Three additional variants within the same gene also predict less severe forms of CAD (46). MEF2A was discovered following up on a linkage peak at 15q26 in a genome-wide scan for MI and CAD (45). A linkage peak in a similar region was identified in one genome scan for major depression (40).

MPO
Myeloperoxydase is an enzyme involved in the production of free radicals, triggering an inflammatory response. A single nucleotide polymorphism has been identified in the promoter region (an A to G substitution at position –463) that appears to increase the rate of enzyme production (129). The G/G genotype at this locus was more common among patients with angiographically documented CAD, compared with matched controls (130). It has also been associated with cardiovascular disease among end stage renal patients (131) and reduced coronary reserve flow in a sample of healthy young men (132). In one study, however, the A allele was associated with larger areas of fibrotic plaque and calcified plaque on autopsy (131). The MPO gene has not been examined in relation to depression.

IL-6
Interleukin-6 is a pro-inflammatory cytokine implicated in both atherosclerosis and depression. A functional SNP (G to C substitution at position –174) in the promoter region of the gene that codes for IL-6 (IL6) has received substantial interest (133). In investigations of functionality, cells transfected with the C allele at position –174 show reduced basal IL-6 expression and a markedly blunted IL-6 response to lipopolysaccharide or IL-1 stimulation than cells transfected with the G allele at this site (134). In epidemiological studies, the C allele at this locus has generally been associated with increased cardiovascular risk. For example, the C allele has been shown to predict elevated IL-6 levels (135,136), change in IL-6 after coronary artery bypass surgery (137), CRP levels (138,139), blood pressure (140,141), left ventricular hypertrophy (140), subclinical carotid intima-media thickness and plaque (135,142), CAD (136,141), and myocardial infarction (143). Nonetheless, no association of this polymorphism with CAD and MI was found in two studies (144,145), while the G/G genotype was associated with increased risk of MI in a third (146).

CRP
A genetic association of CRP concentrations with CAD may be inferred from its association with occurrence of myocardial infarction in first-degree relatives (147). In addition, several polymorphisms have been identified in the genetic precursor of CRP (148,149), one of which, a T to C substitution in the promoter region, has been associated with Type II diabetes among Pima Indians (149). In the only study of cardiovascular disease, however, a 1059G/C exonic variant was not associated with plasma CRP concentrations or risk of developing arterial thrombosis, as defined by MI, stroke, or cardiovascular death (150).

ICAM-1
The gene that codes for intercellular adhesion molecule-1 (ICAM-1) contains a C to T single nucleotide polymorphism in exon 6, resulting in a glutamic acid to lycine substitution at codon 469 (151). The T allele was more common among patients with angiographically documented CAD (151) and patients with probable vascular dementia (152), as compared with controls. However, the C allele appeared to confer risk for ischemic stroke (152) and restenosis following angioplasty (153) in other studies.

VCAM-1
Vascular cell adhesion molecule is a cytokine-inducible adhesion molecule expressed by activated endothelial cells. A role of variation in this gene in human cardiovascular disease may be inferred from animal studies in which a partial deletion of the VCAM-1 gene in an apolipoprotein E knockout mouse results in a marked reduction of monocyte adherence to the endothelium and fatty streak formation (154).

SELE
E-selectin is thought to play a key role in facilitating the attachment of leukocytes to endothelial cells. A single nucleotide polymorphism causing a change in amino acid sequence (serine to arginine at position 128) appears to result in decreased binding specificity (155). The arginine allele at this locus has been associated with a higher risk for CAD and early atherosclerosis (156,157), severity of atherosclerotic disease (158), and restenosis after angioplastly (159). However, no association with CAD was found in one study of patients with Type II diabetes (160).

SELP
P-selectin is an adhesion molecule that mediates the interaction of activated endothelial cells with platelets and leukocytes. Although several polymorphisms have been identified within the gene that codes for P-selectin (SELP), one, an A to C substitution resulting in an amino acid substitution from threonine to proline at position 715, has been associated with a "protective" effect on rate of MI (161). These results were replicated in a second study (162) but not a third (163). A valine to leucine substitution at position 640 has also been shown to predict incidence of ischemic stroke in a population based sample of men (164).

Serotonin
Serotonin is synthesized from tryptophan via tryptophan hydroxylase (TPH) and L-aromatic amino-acid decarboxylase. Serotonin receptors are categorized into seven primary categories (5-HT1-7), among which the 5-HT1 receptor is further divided into subclasses of A, B, D, E, and F and the 5-HT2 receptors are classified as A, B, and C (165). The serotonin transporter serves to uptake 5-HT into the presynaptic neuron or platelets, while monoamine oxydase A is involved in the breakdown of 5-HT in the synaptic cleft. Serotonin gene variants have been examined primarily in relation to depression. Existing studies are reviewed below, beginning with the serotonin genes that have been studied in relation to cardiovascular disease (5-HTT, 5-HT2A, 5-HT2B), followed by genes of interest that, to our knowledge, have not yet been investigated in relation to cardiovascular disease (TPH1, TPH2, 5-HT1A, MAO-A). We do not include investigations of the effects of genetic variants on treatment response to pharmacological agents as they have recently been reviewed elsewhere (165). It should also be noted that several negative studies of individual variants within genes that have not commonly been studied in relation to depression, including 5- HT2C, 5-HT1D, MAO-B (166, 167), and 5-HT6 (168,169), are not described in detail. In addition, although initial associations with depression were reported for variants within 5-HT1B (170) and 5-HT5 (171) in mixed psychiatric samples, nonreplications have also been reported (167,172).

5-HTT (SLC6A4)
A 44-base pair insertion/deletion polymorphism in the transcriptional control region of 5-HTT has been identified (173). Functionally, the deletion polymorphism ("s," or short allele) at this serotonin transporter-linked polymorphic region (5-HTTLPR) appears to cause a reduction in basal and stimulated transcription activity, 5-HTT mRNA, and 5-HT binding and uptake (174). The s allele also predicts blunted prolactin response to clomipramine (175) and lower CSF 5-HIAA (176).

With regard to effects on psychiatic phenotypes, the s allele in the 5-HTT promoter has most consistently been associated with measures of anxiety and neuroticism (174,177–179). Investigations of association with depression have yielded conflicting results. A recent meta-analysis of the association between 5-HTTLPR and depression concluded that there is no significant effect of genotype on unipolar depression (180), but it was subsequently argued that sample sizes of the studies included may have precluded detection of effect (181). Since the meta-analysis, three studies with relatively large sample sizes have been published, one finding an association between 5-HTTLPR (181), an effect found neither in a study of similar sample size and ethnic composition (182) nor in a two homogeneous samples with sample sizes sufficient to detect an effect accounting for 0.5% of the variance at 100% power (183).

Although the main effect of 5-HTTLPR on depression remains in question, there is a growing literature indicating that the insertion/deletion polymorphism interacts with environmental adversity to predict depression. In the first study, by Caspi and colleagues, the s allele interacted with childhood maltreatment and stressful life events to predict major depression in young adulthood (184). Several replications have now been reported. The s allele at 5-HTTLPR has been shown to interact with: 1) maltreatment to predict depressive symptoms in childhood (185), an effect that is blunted by social support; 2) a combined measure of life events and threat to predict depressive symptoms in female but not male adolescents (186); 3) stressful life events to predict major depression in adult twins (187); 4) hip fracture, a common stressful medical event, to predict depressive symptoms (188); and 5) unemployment and chronic disease burden to predict distress in female but not male adults (189). Sixth and seventh studies, however, did not find an interaction between 5-HTTLPR genotype and stressful life events or social adversity in predicting major depression among adults (190,191).

With regard to CAD, the s allele has been shown to occur less frequently among patients with CAD (192) or history of MI (193,194), relative to the "l," or long allele. However, a third study suggested that cardiac risk was greatest among l/s heterozygotes (195). There have been no studies to date to examine whether this genetic variant may interact with stressful life events to predict CAD. However, Grabe and colleagues found chronic disease burden to interact with 5-HTTLPR to predict distress, suggesting that the occurrence of an MI, certainly consistent with substantial disease burden and life stress, may interact with genotype at 5-HTTLPR to differentially affect risk of depression in post-MI patients. This type of hypothesis remains to be tested (196).

The common polymorphism (5-HTTLPR) in the transcriptional control region of the serotonin transporter gene has also been studied in relation to cardiovascular reactivity. In a first study, individuals carrying two copies of the short(s) allele showed blunted heart rate and blood pressure elevations in response to an anger challenge (176). Nonetheless, in a second study (197), the main effect of genotype was in the opposite direction and qualified by a sex interaction.

5-HT2A
5-HT2A has typically been studied in relation to response to clozapine and substance abuse (198). A T to C substitution at position 102 in 5-HT2A has been the primary target of study, although the functional significance of this variant remains in question (199,200). The C allele at position 102 has been associated with a seasonal pattern of major depression (201) and suicide attempts among depressed patients (202). Nonetheless, the latter study and 4 additional case-control studies (203–206) showed no differences in T102C genotype by depression status. Two studies have examined the role of the T102C polymorphism in risk for MI. In the first, the prevalence of TT genotype was significantly higher among cases than controls (207). However, in the second, the T102C polymorphism did not differ across MI cases and controls (193). Finally, a G to A polymorphism at position –1438 in the promoter region of 5-HT2 has also been associated with depressed mood in elderly twins (208) and among Korean adults (209).

5-HT2B
Although no candidate gene studies have been conducted, 5-HT2B is implicated as a positional candidate due to a location near linkage peaks found in one study of depression (37) and one study of MI (210). In addition, the 5-HT2B receptor has been shown to affect cardiac development and cardiac hypertrophy induced by sympathetic agonists in animal models (100,101).

TPH1
Walther and colleagues (211) reported that mice genetically deficient for TPH1 express normal amounts of 5-HT in the brain. As a result, they identified a novel TPH gene, TPH2, expressed primarily in the brain, with TPH1 expressed primarily in the periphery in the mice. This led to suggestions that TPH1 was unlikely to be related to behavioral phenotypes. Nonetheless, recent work by Zill and colleagues (212,213) examined TPH1 and 2 expression in postmortem human brains. Results indicated that both TPH1 and TPH2 are expressed in the human brain but that levels of expression differ in specific brain structures. For example, there is a high expression level of TPH2 in the raphe nuclei, nearly fourfold greater than the expression of TPH1. Nonetheless, TPH1 shows significantly greater expression in the hypothalamus and amygdala.

With regard to genetic variants within TPH1, an A to C SNP at position 218 in intron 7, previously associated with a pharmacological index of central 5-HT responsivity, prolactin response to fenfluramine (214), was associated with depressive symptoms in a sample of Chinese participants (215) and anxiety symptoms in depressed patients (216). However, no association between the A to C variant and depression was observed in the latter study and one additional study (166,216). In addition, an intronic microsatellite repeat upstream from TPH2 predicted a combined measure of depression and anxiety (167), while a second polymorphism in intron 7, A779C, predicted major depression in Swedish patients (217).

TPH2
TPH2 is an isoform of TPH that has been shown to be expressed in brains of both mice and humans (211–213). Two recent papers indicate that variation in this gene may predict major depression. First, a G1463A SNP, associated with a change in amino acid from arginine to histamine at codon 441 and 80% lower 5-HT levels in vitro, was more common among depressed patients than controls (43). In addition, an A to G substitution (rs1386494) in an intronic, or noncoding region, was associated with both major depression (218) and completed suicide (219), effects that were stronger in haplotype analyses, or analyses that examine a number of jointly inherited SNPs as a block. Although the latter SNP does not appear to be functional, the significant haplotype results indicate that this SNP may be located close to a functional variant.

5-HT1A
The 5-HT1A receptor regulates 5-HT neuronal firing thought to play a role in antidepressant response. A promoter region polymorphism, C-1019G, associated with depressed 5-HT1A receptor expression, was significantly more common among depressed cases relative to controls (220). Nonetheless, this polymorphism and three additional variants within 5-HT1A showed no difference in allele frequency between depressed patients and controls in a second study (221).

MAO-A
Two variants within MAO-A have been examined in relation to depression. The first, a silent SNP detected by the introduction of the restriction enzyme EcoRV, has been associated with major depression (222) and depressed suicide (223). In addition, a functional polymorphism relevant to MAO-A activity has been discovered, a 30-base pair variable number tandem repeat sequence present in 3, 3.5, 4, or 5 copies (224). The 3.5 and 4 repeats are associated with a 2.4- to 9.6-fold increase in gene transcription as compared with the 3 and 5 alleles. Although not completely consistent with the functional data, Schultz and colleagues reported that genotypes limited to 3.5, 4, or 5 repeats predicted major depression in females (225). In two other studies, no association was found with major depression (226,227). Finally, the frequency of a 116-base pair repeat of a 2 base pair repeat sequence in intron 2 was greater among female unipolar cases than female bipolar cases (228).

Gene by Gene and Gene by Environment Interaction
From a genetics perspective, both depression and CAD are considered "complex" traits, meaning that the causal pathways are likely to involve multiple genes of small effect, as well as gene by gene and gene by environment interaction (229). From the prior review, it is apparent that the vast majority of studies have focused on the main effects of genetic variants, largely without considering potential gene by gene or gene by environment interaction effects. The obvious exception is the group of studies finding an interaction of the s allele at the promoter variant of the serotonin transporter with life adversity, varying from life events (184) and perceived environmental threat (186,187) to medical events, such as chronic disease (189) and hip fracture (188). These studies suggest potential mechanisms through which gene by environment interaction may result in covariation between depression and CAD. First, as an MI clearly can cause stress and threat, it is possible that it may serve as a life event that triggers depression among those who are vulnerable, such as those carrying the s allele at the serotonin transporter promoter variant. This may result in an increased expression of depression among post-MI patients carrying the s allele. In addition, to the extent that depression plays a causal role in CAD, if the s allele increases risk of depression in response to life events, then this gene by environment interaction may in turn increase the risk for subsequent CAD. A paper by Jerrard-Dunne and colleagues (230) provides an intriguing example of multiple gene effects and gene by environment interaction predicting carotid intima-media thickness (IMT). The authors hypothesized that smoking, a trigger for inflammatory response, would interact with genetic propensity to respond to inflammatory triggers, as defined by a combination of risk alleles within the genes coding for IL-6, IL-1B, IL-1R, and CD14. Genetic vulnerability combined across the four genes had an additive effect on IL-6 levels and IMT (no gene by gene interaction). However, the genetic effects on IL-6 and IMT were limited to smokers, suggesting that an environmental precipitant was necessary to uncover genetic effects related to a propensity for inflammatory response. As it is well known that acute psychological stress elevates IL-6 (231,232) and that elevations of IL-6 are associated with depressive symptomology (83–88), stress or depression may also interact with genetic propensity to respond to inflammatory triggers to predict indices of CAD. Although other models for gene by gene and gene by environment interaction could be proposed, these studies provide examples of how an examination of multiple genes within the same pathway and relevant environmental "triggers" may improve our ability to understand how both genetic and environmental risk are associated with disease endpoints.


   SUMMARY AND INTEGRATION
TOP
 ABSTRACT
 INTRODUCTION
 SUMMARY AND INTEGRATION
NOTES
 REFERENCES
 
In summary, although it is now well established that depression and CAD covary, consideration of the potential for common genetic mechanisms underlying the two disorders has been lacking. In this review, we present literature supporting the hypothesis that common genetic mechanisms underlie depression and CAD comorbidity. As can been seen, there is only one genetically informative study examining both depression and CAD, a twin study finding common genetic variance contributing to both disorders. To date, no linkage or candidate gene association studies have focused on both depression and CAD. For these categories of evidence, we relied on studies examining either depression or CAD. Two linkage intervals for depression and CAD appear to overlap, suggesting that positional candidates in these regions, 2q33 to 35 and 15q25.3 to 26.2, may be of particular interest. In addition, as many candidate genes associated with either depression or CAD are located in pathways of theoretical interest for the other disorder, we interpret these results as suggestive that common genetic influences may affect both depression and CAD.

This review raises many opportunities for future research. For example, genetic targets within the inflammatory pathway show promise as predictors of CAD, but few investigations have examined their potential role in depression. Genetic variation within IL-1B and TNFA have been associated with both depression and CAD, individually. IL-6, MEF2A, MPO, ICAM-1, VCAM-1, SELE, and SELP have not yet been examined in relation to depression despite their location in a pathway of interest.

Two variants within the serotonin pathway have been examined in relation to CAD and depression, although the results are mixed. The l allele at the 5-HTT promoter site has been shown to increase risk for CAD in three of four studies (192–195), while a TT genotype at position 102 in the 5-HT2 gene was associated with risk for MI in one of two studies (193,207). With regard to depression, the 5-HTT promoter variant appears to only influence depression in interaction with life adversity (e.g., 184). Nonetheless, the risk allele associated with depression is the alternative to the l allele, the s allele. Finally, the 5-HT2 variant that has been associated with CAD does not appear related to depression, although there is better evidence for a second variant, a G to A polymorphism at position –1438, which has not yet been examined in relation to CAD. With regard to TPH1, TPH2, 5-HT1A, and MAO-A, results of genetic association have been limited to depression and vary with the specific genetic variant targeted for study. Although some promising results have been obtained, these largely await replication. Overall, research opportunities related to the serotonin pathway (and likely the inflammation pathway and others) will likely involve examination of variants throughout each gene (114), as compared with a single-variant examination of gene by gene and gene by environment interaction (e.g., 188,189), as well as replication of initial results.

Although we chose to highlight two pathways as examples for candidate genes, there are several other pathways hypothesized to contribute to depression and CAD comorbidity (e.g., free fatty acid metabolism, cigarette smoking, stress responsivity), each of which could be broken down into key elements as illustrated for the inflammation and serotonin pathways. Moreover, the "candidate gene" approach, as exemplified in our approach to the inflammation and serotonin pathways, is necessarily limited by our knowledge of the best candidates to select. As our current knowledge of pathways underlying depression and CAD is likely incomplete, the candidate gene approach should be supplemented with genome-wide searches using techniques such as genome-wide association (233).


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 SUMMARY AND INTEGRATION
 NOTES
REFERENCES
 
Supported by HL 77442 (to J.M.M.).

DOI:10.1097/01.psy.0000208630.79271.a0


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUMMARY AND INTEGRATION
 NOTES
 REFERENCES
 

  1. Carney RM, Rich MW, Freedland KE, Saini J, teVelde A, Simeone C, Clark K. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Med 1988;50:627–33.[Abstract/Free Full Text]
  2. Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: Impact on 6-month survival. JAMA 1993;270:1819–25.[Abstract/Free Full Text]
  3. Frasure-Smith N, Lesperance F, Talajic M. The impact of negative emotions on prognosis following myocardial infarction: is it more than depression? Health Psychol 1995;14:388–98.[CrossRef][Medline]
  4. Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003;54:227–40.[CrossRef][Medline]
  5. Carney RM, Freedland KE. Depression, mortality, and medical morbidity in patients with coronary heart disease. Biol Psychiatry 2003;54:241–7.[CrossRef][Medline]
  6. van Melle JP, de Jonge P, Spijkerman TA, Tijssen JG, Ormel J, van Veldhuisen DJ, van den Brink RH, van den Berg MP. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: A meta-analysis. Psychosom Med 2004;66:814–22.[Abstract/Free Full Text]
  7. Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: A meta-analysis. Psychosom Med 2004;66:802–13.[Abstract/Free Full Text]
  8. Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A, Marks J. Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993;4:285–94.[Medline]
  9. Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 1996;93:1976–80.[Abstract/Free Full Text]
  10. Mendes de Leon CF, Krumholz HM, Seeman TS, Vaccarino V, Williams CS, Kasl SV, Berkman LF. Depression and risk of coronary heart disease in elderly men and women: New Haven EPESE, 1982–1991. Established Populations for the Epidemiologic Studies of the Elderly. Arch Intern Med 1998;158:2341–8.[Abstract/Free Full Text]
  11. Murphy E, Smith R, Lindesay J, Slattery J. Increased mortality rates in late-life depression. Br J Psychiatry 1988;152:347–53.[Abstract/Free Full Text]
  12. Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, van Tilburg W. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry 2001;58:221–7.[Abstract/Free Full Text]
  13. Sesso HD, Kawachi I, Vokonas PS, Sparrow D. Depression and the risk of coronary heart disease in the Normative Aging Study. Am J Cardiol 1998;82:851–6.[CrossRef][Medline]
  14. Whooley MA, Browner WS. Association between depressive symptoms and mortality in older women. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1998;158:2129–35.[Abstract/Free Full Text]
  15. Penninx BW, Guralnik JM, Mendes de Leon CF, Pahor M, Visser M, Corti MC, Wallace RB. Cardiovascular events and mortality in newly and chronically depressed persons >70 years of age. Am J Cardiol 1998;81:988–94.[CrossRef][Medline]
  16. Pratt LA, Ford DE, Crum RM, Armenian HK, Gallo JJ, Eaton WW. Depression, psychotropic medication, and risk of myocardial infarction: Prospective data from the Baltimore ECA follow-up. Circulation 1996;94:3123–9.[Abstract/Free Full Text]
  17. Aromaa A, Raitasalo R, Reunanen A, Impivaara O, Heliovaara M, Knekt P, Lehtinen V, Joukamaa M, Maatela J. Depression and cardiovascular diseases. Acta Psychiatr Scand Suppl 1994;377:77–82.[Medline]
  18. Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary artery disease in men: The precursors study. Arch Intern Med 1998;158:1422–6.[Abstract/Free Full Text]
  19. Carney RM, Freeland, Kenneth E, Rich, Michael, W, Jaffe, Allan S. Depression as a risk factor for cardiac events in established coronary heart disease: A review of possible mechanisms. Ann Behav Med 1995;17:142–9.[CrossRef][Medline]
  20. Carney RM, Freedland KE, Miller GE, Jaffe AS. Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. J Psychosom Res 2002;53:897–902.[CrossRef][Medline]
  21. Lesperance F, Frasure-Smith N. The seduction of death. Psychosom Med 1999;61:18–20.[Free Full Text]
  22. Rissanen AM. Familial aggregation of coronary heart disease in a high incidence area (North Karelia, Finland). Br Heart J 1979;42:294–303.[Abstract/Free Full Text]
  23. Rose G. Familial patterns in ischaemic heart disease. Br J Prev Soc Med 1964;18:75–80.[Medline]
  24. Phillips RL, Lilienfeld AM, Diamond EL, Kagan A. Frequency of coronary heart disease and cerebrovascular accidents in parents and sons of coronary heart disease index cases and controls. Am J Epidemiol 1974;100:87–100.[Abstract/Free Full Text]
  25. Slack J, Evans K. The increased risk of death from ischaemic heart disease in first degree relatives of 121 men and 96 women with ischaemic heart disease. J Med Genet 1966;3:239–57.[Free Full Text]
  26. Deutscher S, Ostrander LD, Epstein FH. Familial factors in premature coronary heart disease: A preliminary report from the Tecumseh Community Health Study. Am J Epidemiol 1970;91:233–7.[Abstract/Free Full Text]
  27. Marenberg MER, Berkman N, Gloderus LF, de Faire B. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994;330:1041–6.[Abstract/Free Full Text]
  28. Zdravkovic S, Wienke A, Pedersen NL, Marenberg ME, Yashin AI, de Faire U. Heritability of death from coronary heart disease: A 36-year follow-up of 20 966 Swedish twins. J Intern Med 2002;252:247–54.[CrossRef][Medline]
  29. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: Review and meta-analysis. Am J Psychiatry 2000;157:1552–62.[Abstract/Free Full Text]
  30. Silberg JL, Heath AC, Kessler R, Neale MC, Meyer JM, Eaves LJ, Kendler KS. Genetic and environmental effects on self-reported depressive symptoms in a general population twin sample. J Psychiatr Res 1990;24:197–212.[CrossRef][Medline]
  31. Gatz M, Pedersen NL, Plomin R, Nesselroade JR, McClearn GE. Importance of shared genes and shared environments for symptoms of depression in older adults. J Abnorm Psychol 1992;101:701–8.[Medline]
  32. Carmelli D, Swan GE, Kelly-Hayes M, Wolf PA, Reed T, Miller B. Longitudinal changes in the contribution of genetic and environmental influences to symptoms of depression in older male twins. Psychol Aging 2000;15:505–10.[CrossRef][Medline]
  33. Scherrer JF, Hong X, Bucholz, Kathleen K, Eisen, Seth A, Lyons MJ, Goldberg J, Tsuang M, True W. A twin study of depression symptoms, hypertension, and heart disease in middle-aged men. Psychosom Med 2003;65:548–57.[Abstract/Free Full Text]
  34. Morton NE. Sequential tests for the detection of linkage. Am J Hum Genet 1955;7:277–318.[Medline]
  35. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995;11:241–7.[CrossRef][Medline]
  36. Huezo-Diaz P, Tandon K, Aitchison KJ. The genetics of depression and related traits. Curr Psychiatry Rep 2005;7:117–24.[Medline]
  37. Zubenko GS, Hughes HB, Stiffler JS, Zubenko WN, Kaplan BB. Genome survey for susceptibility loci for recurrent, early-onset major depression: results at 10cM resolution. Am J Med Genet 2002;114:413–22.[CrossRef][Medline]
  38. Zubenko GS, Maher B, Hughes HB 3rd, Zubenko WN, Stiffler JS, Kaplan BB, Marazita ML. Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Am J Med Genet B Neuropsychiatr Genet 2003;123:1–18.[Medline]
  39. Abkevich V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC, Plenk AM, Lowry MR, Richards RL, Carter C, Frech GC, Stone S, Rowe K, Chau CA, Cortado K, Hunt A, Luce K, O'Neil G, Poarch J, Potter J, Poulsen GH, Saxton H, Bernat-Sestak M, Thompson V, Gutin A, Skolnick MH, Shattuck D, Cannon-Albright L. Predisposition locus for major depression at chromosome 12q22–12q23.2. Am J Hum Genet 2003;73:1271–81.[CrossRef][Medline]
  40. Holmans P, Zubenko GS, Crowe RR, DePaulo JR Jr, Scheftner WA, Weissman MM, Zubenko WN, Boutelle S, Murphy-Eberenz K, MacKinnon D, McInnis MG, Marta DH, Adams P, Knowles JA, Gladis M, Thomas J, Chellis J, Miller E, Levinson DF. Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q. Am J Hum Genet 2004;74:1154–67.[CrossRef][Medline]
  41. Hamet P, Tremblay J. Genetics and genomics of depression. Metabolism 2005;54:10–5.[CrossRef][Medline]
  42. Fullerton J, Cubin M, Tiwari H, Wang C, Bomhra A, Davidson S, Miller S, Fairburn C, Goodwin G, Neale MC, Fiddy S, Mott R, Allison DB, Flint J. Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am J Hum Genet 2003;72:879–90.[CrossRef][Medline]
  43. Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 2005;45:11–6.[CrossRef][Medline]
  44. Wang Q. Molecular genetics of coronary artery disease. Curr Opin Cardiol 2005;20:182–8.[CrossRef][Medline]
  45. Wang L, Fan C, Topol SE, Topol EJ, Wang Q. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science 2003;302:1578–81.[Abstract/Free Full Text]
  46. Bhagavatula MR, Fan C, Shen GQ, Cassano J, Plow EF, Topol EJ, Wang Q. Transcription factor MEF2A mutations in patients with coronary artery disease. Hum Mol Genet 2004;13:3181–8.[Abstract/Free Full Text]
  47. Botstein D, Risch N. Discovering genotypes underlying human phenotypes: Past successes for mendelian disease, future approaches for complex disease. Nat Genet 2003;33(suppl):228–37.[CrossRef][Medline]
  48. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry 1998;55:580–92.[Abstract/Free Full Text]
  49. Joynt KE, Whellan DJ, O'Connor CM. Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiatry 2003;54:248–61.[CrossRef][Medline]
  50. Lett HS, Blumenthal JA, Babyak MA, Sherwood A, Strauman T, Robins C, Newman MF. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med 2004;66:305–15.[Abstract/Free Full Text]
  51. Lerman C, Berrettini W. Elucidating the role of genetic factors in smoking behavior and nicotine dependence. Am J Med Genet B Neuropsychiatr Genet 2003;118:48–54.[Medline]
  52. Finley JC Jr, O'Leary M, Wester D, MacKenzie S, Shepard N, Farrow S, Lockette W. A genetic polymorphism of the alpha2-adrenergic receptor increases autonomic responses to stress. J Appl Physiol 2004;96:2231–9.[Abstract/Free Full Text]
  53. Li GH, Faulhaber HD, Rosenthal M, Schuster H, Jordan J, Timmermann B, Hoehe MR, Luft FC, Busjahn A. Beta-2 adrenergic receptor gene variations and blood pressure under stress in normal twins. Psychophysiology 2001;38:485–9.[CrossRef][Medline]
  54. McCaffery JM, Pogue-Geile M, Ferrell R, Petro N, Manuck SB. Variability within {alpha}- and ß-adrenoreceptor genes as predictors of cardiovascular function at rest and in response to mental challenge. J Hypertens 2002;20:1105–14.[CrossRef][Medline]
  55. Wust S, Federenko IS, van Rossum EF, Koper JW, Kumsta R, Entringer S, Hellhammer DH. A psychobiological perspective on genetic determinants of hypothalamus-pituitary-adrenal axis activity. Ann NY Acad Sci 2004;1032:52–62.[CrossRef][Medline]
  56. Wust S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab 2004;89:565–73.[Abstract/Free Full Text]
  57. Neumann SA, Lawrence EC, Jennings JR, Ferrell RE, Manuck SB. Heart rate variability is associated with polymorphic variation in the choline transporter gene. Psychosom Med 2005;67:168–71.[Abstract/Free Full Text]
  58. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Kunzel HE, Fuchs B, Majer M, Pfennig A, Kern N, Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B, Rupprecht R, Messer T, Kohnlein O, Dabitz H, Bruckl T, Muller N, Pfister H, Lieb R, Mueller JC, Lohmussaar E, Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T, Holsboer F, Muller-Myhsok B. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004;36:1319–25.[CrossRef][Medline]
  59. van West D, Del-Favero J, Aulchenko Y, Oswald P, Souery D, Forsgren T, Sluijs S, Bel-Kacem S, Adolfsson R, Mendlewicz J, Van Duijn C, Deboutte D, Van Broeckhoven C, Claes S. A major SNP haplotype of the arginine vasopressin 1B receptor protects against recurrent major depression. Mol Psychiatry 2004;9:287–92.[CrossRef][Medline]
  60. Covault J, Pettinati H, Moak D, Mueller T, Kranzler HR. Association of a long-chain fatty acid-CoA ligase 4 gene polymorphism with depression and with enhanced niacin-induced dermal erythema. Am J Med Genet B Neuropsychiatr Genet 2004;127:42–7.[Medline]
  61. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135–43.[Abstract/Free Full Text]
  62. Libby P, Ridker PM. Novel inflammatory markers of coronary risk: theory versus practice. Circulation 1999;100:1148–50.[Free Full Text]
  63. Harris TB, Ferrucci L, Tracy RP, Corti MC, Wacholder S, Ettinger WH Jr, Heimovitz H, Cohen HJ, Wallace R. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 1999;106:506–12.[CrossRef][Medline]
  64. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767–72.[Abstract/Free Full Text]
  65. Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation 2000;101:2149–53.[Abstract/Free Full Text]
  66. Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr, Boerwinkle E. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: The Atherosclerosis Risk In Communities (ARIC) study. Circulation 1997;96:4219–25.[Abstract/Free Full Text]
  67. Malik I, Danesh J, Whincup P, Bhatia V, Papacosta O, Walker M, Lennon L, Thomson A, Haskard D. Soluble adhesion molecules and prediction of coronary heart disease: A prospective study and meta-analysis. Lancet 2001;358:971–6.[CrossRef][Medline]
  68. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–9.[Abstract/Free Full Text]
  69. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836–43.[Abstract/Free Full Text]
  70. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study: Multiple Risk Factor Intervention Trial. Am J Epidemiol 1996;144:537–47.[Abstract/Free Full Text]
  71. Tracy RP, Lemaitre RN, Psaty BM, Ives DG, Evans RW, Cushman M, Meilahn EN, Kuller LH. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly: Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 1997;17:1121–7.[Abstract/Free Full Text]
  72. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:731–3.[Abstract/Free Full Text]
  73. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, Gallimore JR, Pepys MB. Low grade inflammation and coronary heart disease: Prospective study and updated meta-analyses. BMJ 2000;321:199–204.[Abstract/Free Full Text]
  74. Ozeren A, Aydin M, Tokac M, Demircan N, Unalacak M, Gurel A, Yazici M. Levels of serum IL-1beta, IL-2, IL-8 and tumor necrosis factor-alpha in patients with unstable angina pectoris. Mediators Inflamm 2003;12:361–5.[CrossRef][Medline]
  75. Simon A, Yazdani S, Wang W, Schwartz A, Rabbani L. Circulating levels of IL-1beta, a prothrombotic cytokine, are elevated in unstable angina versus stable angina. J Thromb Thrombolysis 2000;9:217–22.[CrossRef][Medline]
  76. Wang YN, Che SM, Ma AQ. Clinical significance of serum cytokines IL-1beta, sIL-2R, IL-6, TNF-alpha, and IFN-v in acute coronary syndrome. Chin Med Sci J 2004;19:120–4.[Medline]
  77. Fang L, Wei H, Mak KH, Xiong Z, Song J, Wang D, Lim YL, Chatterjee S. Markers of low-grade inflammation and soluble cell adhesion molecules in Chinese patients with coronary artery disease. Can J Cardiol 2004;20:1433–8.[Medline]
  78. Hajilooi M, Sanati A, Ahmadieh A, Ghofraniha A, Massoud A. Circulating ICAM-1, VCAM-1, E-selectin, P-selectin, and TNFRII in patients with coronary artery disease. Immunol Invest 2004;33:263–75.[CrossRef][Medline]
  79. Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: Effects of an early invasive or noninvasive strategy. JAMA 2001;286:2107–13.[Abstract/Free Full Text]
  80. Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid, a protein in severe unstable angina. N Engl J Med 1994;331:417–24.[Abstract/Free Full Text]
  81. Haim M, Tanne D, Boyko V, Reshef T, Goldbourt U, Leor J, Mekori YA, Behar S. Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease: Data from the Bezafibrate Infarction Prevention (BIP) Study. J Am Coll Cardiol 2002;39:1133–8.[Abstract/Free Full Text]
  82. Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001;104:1336–42.[Abstract/Free Full Text]
  83. Miller GE, Stetler CA, Carney RM, Freedland KE, Banks WA. Clinical depression and inflammatory risk markers for coronary heart disease. Am J Cardiol 2002;90:1279–83.[CrossRef][Medline]
  84. Maes M, Vandoolaeghe E, Ranjan R, Bosmans E, Bergmans R, Desnyder R. Increased serum interleukin-1-receptor-antagonist concentrations in major depression. J Affect Disord 1995;36:29–36.[CrossRef][Medline]
  85. Kiecolt-Glaser JK, Glaser R. Depression and immune function: Central pathways to morbidity and mortality. J Psychosom Res 2002;53:873–6.[CrossRef][Medline]
  86. Lutgendorf SK, Garand L, Buckwalter KC, Reimer TT, Hong SY, Lubaroff DM. Life stress, mood disturbance, and elevated interleukin-6 in healthy older women. J Gerontol A Biol Sci Med Sci 1999;54:M434–9.[Abstract]
  87. Dentino AN, Pieper CF, Rao MK, Currie MS, Harris T, Blazer DG, Cohen HJ. Association of interleukin-6 and other biologic variables with depression in older people living in the community. J Am Geriatr Soc 1999;47:6–11.[Medline]
  88. Moreno FA, Rowe DC, Kaiser B, Chase D, Michaels T, Gelernter J, Delgado PL. Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion. Mol Psychiatry 2002;7:213–6.[CrossRef][Medline]
  89. Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowicz K. Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann NY Acad Sci 1995;762:474–6.[Medline]
  90. Danner M, Kasl SV, Abramson JL, Vaccarino V. Association between depression and elevated C-reactive protein. Psychosom Med 2003;65:347–56.[Abstract/Free Full Text]
  91. Lesperance F, Frasure-Smith N, Theroux P, Irwin M. The association between major depression and CRP in patients with recent acute coronary syndromes. In Preparation.
  92. Lesperance F, Frasure-Smith N, Theroux P, Irwin M. The association between major depression, sICAM-1, interleukin-6 and CRP in patients with recent acute coronary syndromes. Am J Psychiatry; in Press.
  93. Rajagopalan S, Brook R, Rubenfire M, Pitt E, Young E, Pitt B. Abnormal brachial artery flow-mediated vasodilation in young adults with major depression. Am J Cardiol 2001;88:196.[CrossRef][Medline]
  94. Bluthe RM, Laye S, Michaud B, Combe C, Dantzer R, Parnet P. Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: A study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci 2000;12:4447–56.[CrossRef][Medline]
  95. Bluthe RM, Michaud B, Poli V, Dantzer R. Role of IL-6 in cytokine-induced sickness behavior: A study with IL-6 deficient mice. Physiol Behav 2000;70:367–73.[CrossRef][Medline]
  96. Kalia M. Neurobiological basis of depression: An update. Metabolism 2005;54:24–7.[Medline]
  97. De Clerck F. Effects of serotonin on platelets and blood vessels. J Cardiovasc Pharmacol 1991;17(suppl):1–5.[Medline]
  98. Nagatomo T, Rashid M, Abul Muntasir H, Komiyama T. Functions of 5-HT2A receptor and its antagonists in the cardiovascular system. Pharmacol Ther 2004;104:59–81.[Medline]
  99. Pakala R, Willerson JT, Benedict CR. Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth muscle cell proliferation. Circulation 1997;96:2280–6.[Abstract/Free Full Text]
  100. Jaffre F, Callebert J, Sarre A, Etienne N, Nebigil CG, Launay JM, Maroteaux L, Monassier L. Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: Control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts. Circulation 2004;110:969–74.[Abstract/Free Full Text]
  101. Nebigil CG, Jaffre F, Messaddeq N, Hickel P, Monassier L, Launay JM, Maroteaux L. Overexpression of the serotonin 5-HT2B receptor in heart leads to abnormal mitochondrial function and cardiac hypertrophy. Circulation 2003;107:3223–9.[Abstract/Free Full Text]
  102. Arora RC, Meltzer HY. Increased serotonin2 (5-HT2) receptor binding as measured by 3H-lysergic acid diethylamide (3H-LSD) in the blood platelets of depressed patients. Life Sci 1989;44:725–34.[CrossRef][Medline]
  103. Biegon A, Grinspoon A, Blumenfeld B, Bleich A, Apter A, Mester R. Increased serotonin 5-HT2 receptor binding on blood platelets of suicidal men. Psychopharmacology (Berl) 1990;100:165–7.[CrossRef][Medline]
  104. Biegon A, Weizman A, Karp L, Ram A, Tiano S, Wolff M. Serotonin 5-HT2 receptor binding on blood platelets–a peripheral marker for depression? Life Sci 1987;41:2485–92.[CrossRef][Medline]
  105. Briley MS, Langer SZ, Raisman R, Sechter D, Zarifian E. Tritiated imipramine binding sites are decreased in platelets of untreated depressed patients. Science 1980;209:303–5.[Abstract/Free Full Text]
  106. Langer SZ, Zarifian E, Briley M, Raisman R, Sechter D. High-affinity binding of 3H-imipramine in brain and platelets and its relevance to the biochemistry of affective disorders. Life Sci 1981;29:211–20.[CrossRef][Medline]
  107. Paul SM, Rehavi M, Skolnick P, Ballenger JC, Goodwin FK. Depressed patients have decreased binding of tritiated imipramine to platelet serotonin ‘transporter.’ Arch Gen Psychiatry 1981;38:1315–7.[Abstract/Free Full Text]
  108. Nemeroff CB, Knight DL, Franks J, Craighead WE, Krishnan KR. Further studies on platelet serotonin transporter binding in depression. Am J Psychiatry 1994;151:1623–5.[Abstract/Free Full Text]
  109. Nemeroff CB, Knight DL, Krishnan RR, Slotkin TA, Bissette G, Melville ML, Blazer DG. Marked reduction in the number of platelet-tritiated imipramine binding sites in geriatric depression. Arch Gen Psychiatry 1988;45:919–23.[Abstract/Free Full Text]
  110. Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: Focus on the serotonin transporter. Clin Chem 1994;40:288–95.[Abstract/Free Full Text]
  111. Musselman DL, Tomer A, Manatunga AK, Knight BT, Porter MR, Kasey S, Marzec U, Harker LA, Nemeroff CB. Exaggerated platelet reactivity in major depression. Am J Psychiatry 1996;153:1313–7.[Abstract/Free Full Text]
  112. Laghrissi-Thode F, Wagner WR, Pollock BG, Johnson PC, Finkel MS. Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry 1997;42:290–5.[CrossRef][Medline]
  113. Serebruany VL, Glassman AH, Malinin AI, Nemeroff CB, Musselman DL, van Zyl LT, Finkel MS, Krishnan KR, Gaffney M, Harrison W, Califf RM, O'Connor CM. Platelet/endothelial biomarkers in depressed patients treated with the selective serotonin reuptake inhibitor sertraline after acute coronary events: The Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy. Circulation 2003;108:939–44.[Abstract/Free Full Text]
  114. Neale BM, Sham PC. The future of association studies: Gene-based analysis and replication. Am J Hum Genet 2004;75:353–62.[CrossRef][Medline]
  115. Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2003;23:656–60.[Abstract/Free Full Text]
  116. Lee BC, Ahn SY, Doo HK, Yim SV, Lee HJ, Jin SY, Hong SJ, Lee SH, Kim SD, Seo JC, Leem KH, Chung JH. Susceptibility for ischemic stroke in Korean population is associated with polymorphisms of the interleukin-1 receptor antagonist and tumor necrosis factor-alpha genes, but not the interleukin-1beta gene. Neurosci Lett 2004;357:33–6.[CrossRef][Medline]
  117. Vohnout B, Di Castelnuovo A, Trotta R, D'Orazi A, Panniteri G, Montali A, Donati MB, Arca M, Iacoviello L. Polymorphisms and risk of coronary artery disease. Clin Sci (Lond) 2002;103:303–10.[Medline]
  118. Fertuzinhos SM, Oliveira JR, Nishimura AL, Pontual D, Carvalho DR, Sougey EB, Otto PA, Zatz M. Analysis of IL-1alpha, IL-1beta, and IL-1RA [correction of IL-RA] polymorphisms in dysthymia. J Mol Neurosci 2004;22:251–6.[CrossRef][Medline]
  119. Yu YW, Chen TJ, Hong CJ, Chen HM, Tsai SJ. Association study of the interleukin-1 beta (C-511T) genetic polymorphism with major depressive disorder, associated symptomatology, and antidepressant response. Neuropsychopharmacology 2003;28:1182–5.[Medline]
  120. McCulley MC, Day IN, Holmes C. Association between interleukin 1-beta promoter (-511) polymorphism and depressive symptoms in Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet 2004;124:50–3.[Medline]
  121. Allen RA, Lee EM, Roberts DH, Park BK, Pirmohamed M. Polymorphisms in the TNF-alpha and TNF-receptor genes in patients with coronary artery disease. Eur J Clin Invest 2001;31:843–51.[CrossRef][Medline]
  122. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997;94:3195–9.[Abstract/Free Full Text]
  123. Tomasdottir H, Hjartarson H, Ricksten A, Wasslavik C, Bengtsson A, Ricksten SE. Tumor necrosis factor gene polymorphism is associated with enhanced systemic inflammatory response and increased cardiopulmonary morbidity after cardiac surgery. Anesth Analg 2003;97:944–9.[Abstract/Free Full Text]
  124. Nicaud V, Raoux S, Poirier O, Cambien F, O'Reilly DS, Tiret L. The TNF alpha/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease: The European Atherosclerosis Research Study II. Atherosclerosis 2002;161:317–25.[CrossRef][Medline]
  125. Dalziel B, Gosby AK, Richman RM, Bryson JM, Caterson ID. Association of the TNF-alpha -308 G/A promoter polymorphism with insulin resistance in obesity. Obes Res 2002;10:401–7.[Medline]
  126. Vendrell J, Fernandez-Real JM, Gutierrez C, Zamora A, Simon I, Bardaji A, Ricart W, Richart C. A polymorphism in the promoter of the tumor necrosis factor-alpha gene (-308) is associated with coronary heart disease in type 2 diabetic patients. Atherosclerosis 2003;167:257–64.[CrossRef][Medline]
  127. Jeanmonod P, von Kanel R, Maly FE, Fischer JE. Elevated Plasma C-reactive protein in chronically distressed subjects who carry the A allele of the TNF-alpha -308 G/A polymorphism. Psychosom Med 2004;66:501–6.[Abstract/Free Full Text]
  128. Jun TY, Pae CU, Hoon H, Chae JH, Bahk WM, Kim KS, Serretti A. Possible association between -G308A tumour necrosis factor-alpha gene polymorphism and major depressive disorder in the Korean population. Psychiatr Genet 2003;13:179–81.[CrossRef][Medline]
  129. Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF. An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem 1996;271:14412–20.[Abstract/Free Full Text]
  130. Nikpoor B, Turecki G, Fournier C, Theroux P, Rouleau GA. A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians. Am Heart J 2001;142:336–9.[CrossRef][Medline]
  131. Makela R, Karhunen PJ, Kunnas TA, Ilveskoski E, Kajander OA, Mikkelsson J, Perola M, Penttila A, Lehtimaki T. Myeloperoxidase gene variation as a determinant of atherosclerosis progression in the abdominal and thoracic aorta: an autopsy study. Lab Invest 2003;83:919–25.[CrossRef][Medline]
  132. Makela R, Laaksonen R, Janatuinen T, Vesalainen R, Nuutila P, Jaakkola O, Knuuti J, Lehtimaki T. Myeloperoxidase gene variation and coronary flow reserve in young healthy men. J Biomed Sci 2004;11:59–64.[Medline]
  133. Woods A, Brull DJ, Humphries SE, Montgomery HE. Genetics of inflammation and risk of coronary artery disease: The central role of interleukin-6. Eur Heart J 2000;21:1574–83.[Free Full Text]
  134. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998;102:1369–76.[Medline]
  135. Jerrard-Dunne P, Sitzer M, Risley P, Steckel DA, Buehler A, von Kegler S, Markus HS. Interleukin-6 promoter polymorphism modulates the effects of heavy alcohol consumption on early carotid artery atherosclerosis: The Carotid Atherosclerosis Progression Study (CAPS). Stroke 2003;34:402–7.[Abstract/Free Full Text]
  136. Bruunsgaard H, Christiansen L, Pedersen AN, Schroll M, Jorgensen T, Pedersen BK. The IL-6-174G>C polymorphism is associated with cardiovascular diseases and mortality in 80-year-old humans. Exp Gerontol 2004;39:255–61.[CrossRef][Medline]
  137. Brull DJ, Montgomery HE, Sanders J, Dhamrait S, Luong L, Rumley A, Lowe GD, Humphries SE. Interleukin-6 gene -174g>c and -572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol 2001;21:1458–63.[Abstract/Free Full Text]
  138. Vickers MA, Green FR, Terry C, Mayosi BM, Julier C, Lathrop M, Ratcliffe PJ, Watkins HC, Keavney B. Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein. Cardiovasc Res 2002;53:1029–34.[Abstract/Free Full Text]
  139. Jenny NS, Tracy RP, Ogg MS, Luong le A, Kuller LH, Arnold AM, Sharrett AR, Humphries SE. In the elderly, interleukin-6 plasma levels and the -174G>C polymorphism are associated with the development of cardiovascular disease. Arterioscler Thromb Vasc Biol 2002;22:2066–71.[Abstract/Free Full Text]
  140. Losito A, Kalidas K, Santoni S, Jeffery S. Association of interleukin-6-174G/C promoter polymorphism with hypertension and left ventricular hypertrophy in dialysis patients. Kidney Int 2003;64:616–22.[CrossRef][Medline]
  141. Humphries SE, Luong LA, Ogg MS, Hawe E, Miller GJ. The interleukin-6-174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J 2001;22:2243–52.[Abstract/Free Full Text]
  142. Chapman CM, Beilby JP, Humphries SE, Palmer LJ, Thompson PL, Hung J. Association of an allelic variant of interleukin-6 with subclinical carotid atherosclerosis in an Australian community population. Eur Heart J 2003;24:1494–9.[Abstract/Free Full Text]
  143. Georges JL, Loukaci V, Poirier O, Evans A, Luc G, Arveiler D, Ruidavets JB, Cambien F, Tiret L. Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: The ECTIM study. Etude Cas-Temoin de l'Infarctus du Myocarde. J Mol Med 2001;79:300–5.[CrossRef][Medline]
  144. Nauck M, Winkelmann BR, Hoffmann MM, Bohm BO, Wieland H, Marz W. The interleukin-6 G(-174)C promoter polymorphism in the LURIC cohort: No association with plasma interleukin-6, coronary artery disease, and myocardial infarction. J Mol Med 2002;80:507–13.[CrossRef][Medline]
  145. Lieb W, Pavlik R, Erdmann J, Mayer B, Holmer SR, Fischer M, Baessler A, Hengstenberg C, Loewel H, Doering A, Riegger GA, Schunkert H. No association of interleukin-6 gene polymorphism (-174 G/C) with myocardial infarction or traditional cardiovascular risk factors. Int J Cardiol 2004;97:205–12.[CrossRef][Medline]
  146. Kelberman D, Hawe E, Luong L, Mohamed-Ali V, Lundman P, Tornvall P, Aillaud M, Juhan-Vague I, Yudkin JS, Margaglione M, Di Minno G, Tremoli E, Humphries S. Effect of Interleukin-6 promoter polymorphisms in survivors of myocardial infarction and matched controls in the North and South of Europe: The HIFMECH Study. Thromb Haemost 2004;92:1122–8.[Medline]
  147. Margaglione M, Cappucci G, Colaizzo D, Vecchione G, Grandone E, Di Minno G. C-reactive protein in offspring is associated with the occurrence of myocardial infarction in first-degree relatives. Arterioscler Thromb Vasc Biol 2000;20:198–203.[Abstract/Free Full Text]
  148. Cao H, Hegele RA. Human C-reactive protein (CRP) 1059G/C polymorphism. J Hum Genet 2000;45:100–1.[CrossRef][Medline]
  149. Wolford JK, Gruber JD, Ossowski VM, Vozarova B, Antonio Tataranni P, Bogardus C, Hanson RL. A C-reactive protein promoter polymorphism is associated with type 2 diabetes mellitus in Pima Indians. Mol Genet Metab 2003;78:136–44.[CrossRef][Medline]
  150. Zee RY, Ridker PM. Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis. Atherosclerosis 2002;162:217–9.[CrossRef][Medline]
  151. Jiang H, Klein RM, Niederacher D, Du M, Marx R, Horlitz M, Boerrigter G, Lapp H, Scheffold T, Krakau I, Gulker H. C/T polymorphism of the intercellular adhesion molecule-1 gene (exon 6, codon 469): A risk factor for coronary heart disease and myocardial infarction. Int J Cardiol 2002;84:171–7.[CrossRef][Medline]
  152. Pola R, Flex A, Gaetani E, Papaleo P, De Martini D, Gerardino L, Serricchio M, Pola P, Bernabei R. Association between intercellular adhesion molecule-1 E/K gene polymorphism and probable vascular dementia in humans. Neurosci Lett 2002;326:171–4.[CrossRef][Medline]
  153. Liu Z, Huo Y, Li J, Zhang Y, Xue L, Zhao C, Hong X, Huang A, Gao W. Polymorphism K469E of intercellular adhesion molecule-1 gene and restenosis after coronary stenting in Chinese patients. Physiol Genomics 2004;15:65–74.
  154. Dansky HM, Barlow CB, Lominska C, Sikes JL, Kao C, Weinsaft J, Cybulsky MI, Smith JD. Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler Thromb Vasc Biol 2001;21:1662–7.[Abstract/Free Full Text]
  155. Revelle BM, Scott D, Beck PJ. Single amino acid residues in the E- and P-selectin epidermal growth factor domains can determine carbohydrate binding specificity. J Biol Chem 1996;271:16160–70.[Abstract/Free Full Text]
  156. Wenzel K, Ernst M, Rohde K, Baumann G, Speer A. DNA polymorphisms in adhesion molecule genes: A new risk factor for early atherosclerosis. Hum Genet 1996;97:15–20.[Medline]
  157. Wenzel K, Felix S, Kleber FX, Brachold R, Menke T, Schattke S, Schulte KL, Glaser C, Rohde K, Baumann G. E-selectin polymorphism and atherosclerosis: An association study. Hum Mol Genet 1994;3:1935–7.[Abstract/Free Full Text]
  158. Ghilardi G, Biondi M, Turri O, Guagnellini E, Scorza R. Ser128Arg gene polymorphism for E-selectin and severity of atherosclerotic arterial diesease. Thromb Res 2004;12:47–50.[CrossRef]
  159. Rauchhaus M, Gross M, Schulz S, Francis D, Greiser P, Norwig A, Weidhase L, Dietz R, Anker S, Glaser C. The E-selectin SER128ARG gene polymorphism and restenosis after successful coronary angioplasty. Am J Clin Nutr 2000;71(suppl):213–23.
  160. Endler G, Exner M, Raith M, Marculescu R, Mannhalter C, Endler L, Wojta J, Huber K, Wagner OF. The E-selectin S128R polymorphism is not a risk factor for coronary artery disease in patients with diabetes mellitus type 2. Thromb Res 2003;112:47–50.[CrossRef][Medline]
  161. Herrmann S, Ricard S, Nicaud V, Mallet C, Evans A, Ruidavets JB, Arveiler D, Luc G, Cambien F. The P-selectin gene is highly polymorphic: Reduced frequency of the Pro715 allele carriers in patients with myocardial infarction. Thromb Haemost 2004;92:1060–5.[Medline]
  162. Kee F, Morrison C, Evans AE, McCrum E, McMaster D, Dallongeville J, Nicaud V, Poirier O, Cambien F. Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM extension study: Etude cas-temoin de l'infarctus myocarde. Heart 2000;84:548–52.[Abstract/Free Full Text]
  163. Carter A, Anagnostopoulou K, Mansfield M, Grant P. Soluble P-selectin levels, P-selectin polymorphisms and cardiovascular disease. Hum Mol Genet 2002;11:2015–23.[Abstract/Free Full Text]
  164. Zee RY, Cook N, Cheng S, Reynolds R, Erlich H, Lindpaintner K, Ridker PM. Polymorphism in the P-selectin and interleukin-4 genes as detrerminants of stroke: a population-based, prospective genetic analysis. J Thromb Haemost 2003;1:1718–23.[CrossRef][Medline]
  165. Serretti A, Benedetti F, Zanardi R, Smeraldi E. The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1074–84.[CrossRef][Medline]
  166. Frisch A, Postilnick D, Rockah R, Michaelovsky E, Postilnick S, Birman E, Laor N, Rauchverger B, Kreinin A, Poyurovsky M, Schneidman M, Modai I, Weizman R. Association of unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways. Mol Psychiatry 1999;4:389–92.[CrossRef][Medline]
  167. Nash MW, Sugden K, Huezo-Diaz P, Williamson R, Sterne A, Purcell S, Sham PC, Craig IW. Association analysis of monoamine genes with measures of depression and anxiety in a selected community sample of siblings. Am J Med Genet B Neuropsychiatr Genet 2005;135:33–7.[Medline]
  168. Hong CJ, Tsai SJ, Cheng CY, Liao WY, Song HL, Lai HC. Association analysis of the 5-HT(6) receptor polymorphism (C267T) in mood disorders. Am J Med Genet 1999;88:601–2.[CrossRef][Medline]
  169. Liu HC, Hong CJ, Liu CY, Lin KN, Tsai SJ, Liu TY, Chi CW, Wang PN. Association analysis of the 5-HT6 receptor polymorphism C267T with depression in patients with Alzheimer's disease. Psychiatry Clin Neurosci 2001;55:427–9.[Medline]
  170. Huang YY, Oquendo MA, Friedman JM, Greenhill LL, Brodsky B, Malone KM, Khait V, Mann JJ. Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism. Neuropsychopharmacology 2003;28:163–9.[CrossRef][Medline]
  171. Birkett JT, Arranz MJ, Munro J, Osbourn S, Kerwin RW, Collier DA. Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response. Neuroreport 2000;11:2017–20.[Medline]
  172. Arias B, Collier DA, Gasto C, Pintor L, Gutierrez B, Valles V, Fananas L. Genetic variation in the 5-HT5A receptor gene in patients with bipolar disorder and major depression. Neurosci Lett 2001;303:111–4.[CrossRef][Medline]
  173. Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;66:2621–4.[Medline]
  174. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996;274:1527–31.[Abstract/Free Full Text]
  175. Whale R, Quested DJ, Laver D, Harrison PJ, Cowen PJ. Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine. Psychopharmacology (Berl) 2000;150:120–2.[CrossRef][Medline]
  176. Williams RB, Marchuk DA, Gadde KM, Barefoot JC, Grichnik K, Helms MJ, Kuhn CM, Lewis JG, Schanberg SM, Stafford-Smith M, Suarez EC, Clary GL, Svenson IK, Siegler IC. Central nervous system serotonin function and cardiovascular responses to stress. Psychosom Med 2001;63:300–5.[Abstract/Free Full Text]
  177. Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D, Murphy DL. Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet 2000;96:202–16.[CrossRef][Medline]
  178. Mazzanti CM, Lappalainen J, Long JC, Bengel D, Naukkarinen H, Eggert M, Virkkunen M, Linnoila M, Goldman D. Role of the serotonin transporter promoter polymorphism in anxiety-related traits. Arch Gen Psychiatry 1998;55:936–40.[Abstract/Free Full Text]
  179. Sen S, Burmeister M, Ghosh D. Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet B Neuropsychiatr Genet 2004;127:85–9.[Medline]
  180. Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 2003;8:574–91.[CrossRef][Medline]
  181. Hoefgen B, Schulze TG, Ohlraun S, von Widdern O, Hofels S, Gross M, Heidmann V, Kovalenko S, Eckermann A, Kolsch H, Metten M, Zobel A, Becker T, Nothen MM, Propping P, Heun R, Maier W, Rietschel M. The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biol Psychiatry 2005;57:247–51.[CrossRef][Medline]
  182. Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruc L, Nothen MM, Blackwood D, Muir W, Battersby S, Lerer B, Segman RH, Kaneva R, Serretti A, Lilli R, Lorenzi C, Jakovljevic M, Ivezic S, Rietschel M, Milanova V, Van Broeckhoven C. Serotonin transporter 5-HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet 2004;12:377–82.[CrossRef][Medline]
  183. Willis-Owen SA, Turri MG, Munafo MR, Surtees PG, Wainwright NW, Brixey RD, Flint J. The serotonin transporter length polymorphism, neuroticism, and depression: A comprehensive assessment of association. Biol Psychiatry 2005;58:451–6.[CrossRef][Medline]
  184. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 2003;301:386–9.[Abstract/Free Full Text]
  185. Kaufman J, Yang BZ, Douglas-Palumberi H, Houshyar S, Lipschitz D, Krystal JH, Gelernter J. Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci USA 2004;101:17316–21.[Abstract/Free Full Text]
  186. Eley TC, Sugden K, Corsico A, Gregory AM, Sham P, McGuffin P, Plomin R, Craig IW. Gene-environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry 2004;9:908–15.[CrossRef][Medline]
  187. Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B. The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication. Arch Gen Psychiatry 2005;62:529–35.[Abstract/Free Full Text]
  188. Lenze EJ, Munin MC, Ferrell RE, Pollock BG, Skidmore E, Lotrich F, Rogers JC, Quear T, Houck P, Reynolds CF 3rd. Association of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) genotype with depression in elderly persons after hip fracture. Am J Geriatr Psychiatry 2005;13:428–32.[CrossRef][Medline]
  189. Grabe HJ, Lange M, Wolff B, Volzke H, Lucht M, Freyberger HJ, John U, Cascorbi I. Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Mol Psychiatry 2005;10:220–4.[CrossRef][Medline]
  190. Gillespie NA, Whitfield JB, Williams B, Heath AC, Martin NG. The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychol Med 2005;35:101–111.[CrossRef][Medline]
  191. Surtees PG, Wainwright NW, Willis-Owen SA, Luben R, Day NE, Flint J. Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biol Psychiatry 2005 [Epub ahead of print]
  192. Arinami T, Ohtsuki T, Yamakawa-Kobayashi K, Amemiya H, Fujiwara H, Kawata K, Ishiguro H, Hamaguchi H. A synergistic effect of serotonin transporter gene polymorphism and smoking in association with CHD. Thromb Haemost 1999;81:853–6.[Medline]
  193. Coto E, Reguero JR, Alvarez V, Morales B, Batalla A, Gonzalez P, Martin M, Garcia-Castro M, Iglesias-Cubero G, Cortina A. 5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction. Clin Sci (Lond) 2003;104:241–5.[Medline]
  194. Fumeron F, Betoulle D, Nicaud V, Evans A, Kee F, Ruidavets JB, Arveiler D, Luc G, Cambien F. Serotonin transporter gene polymorphism and myocardial infarction: Etude Cas-Temoins de l'Infarctus du Myocarde (ECTIM). Circulation 2002;105:2943–5.[Abstract/Free Full Text]
  195. Comings DE, MacMurray JP, Gonzalez N, Ferry L, Peters WR. Association of the serotonin transporter gene with serum cholesterol levels and heart disease. Mol Genet Metab 1999;67:248–53.[CrossRef][Medline]
  196. Ramasubbu R. Serotonin transporter gene functional polymorphism: A plausible candidate gene for increased vascular risk in depression. Med Hypotheses 2003;61:36–44.[CrossRef][Medline]
  197. McCaffery JM, Bleil M, Pogue-Geile MF, Ferrell RE, Manuck SB. Allelic variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cardiovascular reactivity in young adult male and female twins of European-American descent. Psychosom Med 2003;65:721–8.[Abstract/Free Full Text]
  198. Veenstra-VanderWeele J, Anderson GM, Cook EH Jr. Pharmacogenetics and the serotonin system: Initial studies and future directions. Eur J Pharmacol 2000;410:165–81.[CrossRef][Medline]
  199. Turecki G, Briere R, Dewar K, Antonetti T, Lesage AD, Seguin M, Chawky N, Vanier C, Alda M, Joober R, Benkelfat C, Rouleau GA. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry 1999;156:1456–8.[Abstract/Free Full Text]
  200. Bray NJ, Buckland PR, Hall H, Owen MJ, O'Donovan MC. The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain. Mol Psychiatry 2004;9:109–14.[CrossRef][Medline]
  201. Arias B, Gutierrez B, Pintor L, Gasto C, Fananas L. Variability in the 5-HT(2A) receptor gene is associated with seasonal pattern in major depression. Mol Psychiatry 2001;6:239–42.[CrossRef][Medline]
  202. Arias B, Gasto C, Catalan R, Gutierrez B, Pintor L, Fananas L. The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients. Am J Med Genet 2001;105:801–4.[CrossRef][Medline]
  203. Khait VD, Huang YY, Zalsman G, Oquendo MA, Brent DA, Harkavy-Friedman JM, Mann JJ. Association of serotonin 5-HT2A receptor binding and the T102C polymorphism in depressed and healthy Caucasian subjects. Neuropsychopharmacology 2005;30:166–72.[CrossRef][Medline]
  204. Minov C, Baghai TC, Schule C, Zwanzger P, Schwarz MJ, Zill P, Rupprecht R, Bondy B. Serotonin-2A-receptor and -transporter polymorphisms: Lack of association in patients with major depression. Neurosci Lett 2001;303:119–22.[CrossRef][Medline]
  205. Oswald P, Souery D, Massat I, Del-Favero J, Linotte S, Papadimitriou G, Dikeos D, Kaneva R, Milanova V, Oruc L, Ivezic S, Serretti A, Lilli R, Van Broeckhoven C, Mendlewicz J. Lack of association between the 5-HT2A receptor polymorphism (T102C) and unipolar affective disorder in a multicentric European study. Eur Neuropsychopharmacol 2003;13:365–8.[CrossRef][Medline]
  206. Tsai SJ, Hong CJ, Hsu CC, Cheng CY, Liao WY, Song HL, Lai HC. Serotonin-2A receptor polymorphism (102T/C) in mood disorders. Psychiatry Res 1999;87:233–7.[CrossRef][Medline]
  207. Yamada S, Akita H, Kanazawa K, Ishida T, Hirata K, Ito K, Kawashima S, Yokoyama M. T102C polymorphism of the serotonin (5-HT) 2A receptor gene in patients with non-fatal acute myocardial infarction. Atherosclerosis 2000;150:143–8.[CrossRef][Medline]
  208. Jansson M, Gatz M, Berg S, Johansson B, Malmberg B, McClearn GE, Schalling M, Pedersen NL. Association between depressed mood in the elderly and a 5-HTR2A gene variant. Am J Med Genet 2003;120:79–84.
  209. Choi MJ, Lee HJ, Lee HJ, Ham BJ, Cha JH, Ryu SH, Lee MS. Association between major depressive disorder and the -1438A/G polymorphism of the serotonin 2A receptor gene. Neuropsychobiology 2004;49:38–41.[CrossRef][Medline]
  210. Harrap SB, Zammit KS, Wong ZY, Williams FM, Bahlo M, Tonkin AM, Anderson ST. Genome-wide linkage analysis of the acute coronary syndrome suggests a locus on chromosome 2. Arterioscler Thromb Vasc Biol 2002;22:874–8.[Abstract/Free Full Text]
  211. Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader M. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003;299:76.[Free Full Text]
  212. Zill P, Buttner A, Eisenmenger W, Bondy B, Ackenheil M. Regional mRNA expression of a second tryptophan hydroxylase isoform in postmortem tissue samples of two human brains. Eur Neuropsychopharmacol 2004;14:282–4.[CrossRef][Medline]
  213. Zill P, Buttner A, Eisenmenger W, Moller HJ, Ackenheil M, Bondy B. Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: A post-mortem study. J Psychiatr Res 2005.
  214. Manuck SB, Flory JD, Ferrell RE, Dent KM, Mann JJ, Muldoon MF. Aggression and anger-related traits associated with a polymorphism of the tryptophan hydroxylase gene. Biol Psychiatry 1999;45:603–14.[CrossRef][Medline]
  215. Tan EC, Chan AO, Tan CH, Mahendran R, Wang A, Chua HC. Case-control and linkage disequilibrium studies of the tryptophan hydroxylase gene polymorphisms and major depressive disorder. Psychiatr Genet 2003;13:151–4.[CrossRef][Medline]
  216. Du L, Bakish D, Hrdina PD. Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder. J Affect Disord 2001;65:37–44.[CrossRef][Medline]
  217. Gizatullin R, Zaboli G, Jonsson EG, Asberg M, Leopardi R. Haplotype analysis reveals tryptophan hydroxylase (TPH) 1 gene variants associated with major depression. Biol Psychiatry 2005 [Epub ahead of print]
  218. Zill P, Baghai TC, Zwanzger P, Schule C, Eser D, Rupprecht R, Moller HJ, Bondy B, Ackenheil M. SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 2004;9:1030–6.[CrossRef][Medline]
  219. Zill P, Buttner A, Eisenmenger W, Moller HJ, Bondy B, Ackenheil M. Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims. Biol Psychiatry 2004;56:581–6.[CrossRef][Medline]
  220. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 2003;23:8788–99.[Abstract/Free Full Text]
  221. Arias B, Arranz MJ, Gasto C, Catalan R, Pintor L, Gutierrez B, Kerwin RW, Fananas L. Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT(1A) receptor gene as putative risk factors in major depression. Mol Psychiatry 2002;7:930–2.[CrossRef][Medline]
  222. Du L, Bakish D, Ravindran A, Hrdina PD. MAO–A gene polymorphisms are associated with major depression and sleep disturbance in males. Neuroreport 2004;15:2097–101.[CrossRef][Medline]
  223. Du L, Faludi G, Palkovits M, Sotonyi P, Bakish D, Hrdina PD. High activity-related allele of MAO–A gene associated with depressed suicide in males. Neuroreport 2002;13:1195–8.[CrossRef][Medline]
  224. Sabol SZ, Hu S, Hamer D. A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998;103:273–9.[CrossRef][Medline]
  225. Schulze TG, Muller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt H, Grassle M, Papassotiropoulos A, Heun R, Nothen MM, Maier W, Lesch KP, Rietschel M. Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder. Am J Med Genet 2000;96:801–3.[CrossRef][Medline]
  226. Gutierrez B, Arias B, Gasto C, Catalan R, Papiol S, Pintor L, Fananas L. Association analysis between a functional polymorphism in the monoamine oxidase A gene promoter and severe mood disorders. Psychiatr Genet 2004;14:203–8.[CrossRef][Medline]
  227. Syagailo YV, Stober G, Grassle M, Reimer E, Knapp M, Jungkunz G, Okladnova O, Meyer J, Lesch KP. Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders. Am J Med Genet 2001;105:168–71.[CrossRef][Medline]
  228. Lin S, Jiang S, Wu X, Qian Y, Wang D, Tang G, Gu N. Association analysis between mood disorder and monoamine oxidase gene. Am J Med Genet 2000;96:12–4.[CrossRef][Medline]
  229. Strachan T, Read AP. Human Molecular Genetics, vol. 2. New York: John Wiley & Sons, 1999.
  230. Jerrard-Dunne P, Sitzer M, Risley P, Buehler A, von Kegler S, Markus HS. Inflammatory gene load is associated with enhanced inflammation and early carotid atherosclerosis in smokers. Stroke 2004;35:2438–43.[Abstract/Free Full Text]
  231. Song C, Kenis G, van Gastel A, Bosmans E, Lin A, de Jong R, Neels H, Scharpe S, Janca A, Yasukawa K, Maes M. Influence of psychological stress on immune-inflammatory variables in normal humans: II. Altered serum concentrations of natural anti-inflammatory agents and soluble membrane antigens of monocytes and T lymphocytes. Psychiatry Res 1999;85:293–303.[CrossRef][Medline]
  232. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical and psychological stressors elevates plasma interleukin 6: Relationship to the activation of hypothalamic-pituitary-adrenal axis. Endocrinology 1993;133:2523–30.[Abstract/Free Full Text]
  233. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science 1996;273:1516–7.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Circ Cardiovasc GenetHome page
S. Su, J. Zhao, J. D. Bremner, A. H. Miller, W. Tang, M. Bouzyk, H. Snieder, O. Novik, N. Afzal, J. Goldberg, et al.
Serotonin Transporter Gene, Depressive Symptoms, and Interleukin-6
Circ Cardiovasc Genet, December 1, 2009; 2(6): 614 - 620.
[Abstract] [Full Text] [PDF]

Home page
 Arch Intern MedHome page
V. Vaccarino, J. Votaw, T. Faber, E. Veledar, N. V. Murrah, L. R. Jones, J. Zhao, S. Su, J. Goldberg, J. P. Raggi, et al.
Major Depression and Coronary Flow Reserve Detected by Positron Emission Tomography
Arch Intern Med, October 12, 2009; 169(18): 1668 - 1676.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
J. Zhao, A. A. Quyyumi, R. Patel, A. M. Zafari, E. Veledar, S. Onufrak, L. H. Shallenberger, L. Jones, and V. Vaccarino
Sex-Specific Association of Depression and a Haplotype in Leukotriene A4 Hydrolase Gene
Psychosom Med, September 1, 2009; 71(7): 691 - 696.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
B. R. Grossardt, J. H. Bower, Y. E. Geda, R. C. Colligan, and W. A. Rocca
Pessimistic, Anxious, and Depressive Personality Traits Predict All-Cause Mortality: The Mayo Clinic Cohort Study of Personality and Aging
Psychosom Med, June 1, 2009; 71(5): 491 - 500.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
R. J. Van Lieshout, J. Bienenstock, and G. M. MacQueen
A Review of Candidate Pathways Underlying the Association Between Asthma and Major Depressive Disorder
Psychosom Med, February 1, 2009; 71(2): 187 - 195.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
S. Su, A. H. Miller, H. Snieder, J. D. Bremner, J. Ritchie, C. Maisano, L. Jones, N. V. Murrah, J. Goldberg, and V. Vaccarino
Common Genetic Contributions to Depressive Symptoms and Inflammatory Markers in Middle-Aged Men: The Twins Heart Study
Psychosom Med, February 1, 2009; 71(2): 152 - 158.
[Abstract] [Full Text] [PDF]

Home page
 Cleveland Clinic Journal of MedicineHome page
L. POZUELO, G. TESAR, J. ZHANG, M. PENN, K. FRANCO, and W. JIANG
Depression and heart disease: What do we know, and where are we headed?
Cleveland Clinic Journal of Medicine, January 1, 2009; 76(1): 59 - 70.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
K. E. Freedland, E. J.C. de Geus, R. N. Golden, W. J. Kop, G. E. Miller, V. Vaccarino, B. Brumback, M. M. Llabre, V. J. White, and D. S. Sheps
What's in a Name? Psychosomatic Medicine and Biobehavioral Medicine
Psychosom Med, January 1, 2009; 71(1): 1 - 4.
[Full Text] [PDF]

Home page
 ESC Textbook of Cardiovascular MedicineHome page
S. S. Pedersen, N. Kupper, and J. Denollet
CHAPTER 35 Psychological Factors and Heart Disease
ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter.
[Abstract] [Full Text] [PDF]

Home page
 Am J EpidemiolHome page
M. Hotopf, M. Henderson, and D. Kuh
Invited Commentary: Stress and Mortality
Am. J. Epidemiol., September 1, 2008; 168(5): 492 - 495.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
V. Vaccarino, R. Lampert, J. D. Bremner, F. Lee, S. Su, C. Maisano, N. V. Murrah, L. Jones, F. Jawed, N. Afzal, et al.
Depressive Symptoms and Heart Rate Variability: Evidence for a Shared Genetic Substrate in a Study of Twins
Psychosom Med, July 1, 2008; 70(6): 628 - 636.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
C. Dickens, L. McGowan, C. Percival, B. Tomenson, L. Cotter, A. Heagerty, and F. Creed
New Onset Depression Following Myocardial Infarction Predicts Cardiac Mortality
Psychosom Med, May 1, 2008; 70(4): 450 - 455.
[Abstract] [Full Text] [PDF]

Home page
 Psychosom. Med.Home page
J. C. Stewart, D. Janicki-Deverts, M. F. Muldoon, and T. W. Kamarck
Depressive Symptoms Moderate the Influence of Hostility on Serum Interleukin-6 and C-Reactive Protein
Psychosom Med, February 1, 2008; 70(2): 197 - 204.
[Abstract] [Full Text] [PDF]

Home page
 Arch Gen PsychiatryHome page
N. Frasure-Smith and F. Lesperance
Depression and Anxiety as Predictors of 2-Year Cardiac Events in Patients With Stable Coronary Artery Disease
Arch Gen Psychiatry, January 1, 2008; 65(1): 62 - 71.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
C. E. Angermann, G. Gelbrich, S. Stork, A. Fallgatter, J. Deckert, H. Faller, G. Ertl, and on behalf of the MOOD-HF Investigators
Rationale and design of a randomised, controlled, multicenter trial investigating the effects of selective serotonin re-uptake inhibition on morbidity, mortality and mood in depressed heart failure patients (MOOD-HF)
Eur J Heart Fail, December 1, 2007; 9(12): 1212 - 1222.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. PsychiatryHome page
C. Otte, J. McCaffery, S. Ali, and M. A. Whooley
Association of a Serotonin Transporter Polymorphism (5-HTTLPR) With Depression, Perceived Stress, and Norepinephrine in Patients With Coronary Disease: The Heart and Soul Study
Am J Psychiatry, September 1, 2007; 164(9): 1379 - 1384.
[Abstract] [Full Text] [PDF]

Home page
 Arch Gen PsychiatryHome page
A. H. Glassman, J. T. Bigger, M. Gaffney, and L. T. Van Zyl
Heart Rate Variability in Acute Coronary Syndrome Patients With Major Depression: Influence of Sertraline and Mood Improvement
Arch Gen Psychiatry, September 1, 2007; 64(9): 1025 - 1031.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
M. F. Muldoon, R. H. Mackey, K. Sutton-Tyrrell, J. D. Flory, B. G. Pollock, and S. B. Manuck
Lower Central Serotonergic Responsivity Is Associated With Preclinical Carotid Artery Atherosclerosis
Stroke, August 1, 2007; 38(8): 2228 - 2233.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
R. von Kanel and S. Begre
Depression After Myocardial Infarction: Unraveling the Mystery of Poor Cardiovascular Prognosis and Role of Beta-Blocker Therapy
J. Am. Coll. Cardiol., December 5, 2006; 48(11): 2215 - 2217.
[Full Text] [PDF]

Home page
 JAMAHome page
M. A. Whooley
Depression and cardiovascular disease: healing the broken-hearted.
JAMA, June 28, 2006; 295(24): 2874 - 2881.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
M. A. Whooley
Mind your heart.
Ann Intern Med, June 6, 2006; 144(11): 858 - 860.
[Full Text] [PDF]

Home page
 Psychosom. Med.Home page
K. E. Freedland, G. E. Miller, and D. S. Sheps
The Great Debate, revisited.
Psychosom Med, March 1, 2006; 68(2): 179 - 184.
[Full Text] [PDF]

Home page
 Psychosom. Med.Home page
E. J. C. de Geus
Genetic pleiotropy in depression and coronary artery disease.
Psychosom Med, March 1, 2006; 68(2): 185 - 186.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by McCaffery, J. M.
Right arrow Articles by Lespérance, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by McCaffery, J. M.
Right arrow Articles by Lespérance, F.
Related Collections
Right arrow Genetics
Right arrow Reviews
Right arrow Coronary Artery Disease

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS