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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
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUMMARY AND INTEGRATIONNOTESREFERENCES |
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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-
= tumor necrosis factor-; 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.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUMMARY AND INTEGRATIONNOTESREFERENCES |
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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- (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- 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.
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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- 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- 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.
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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).
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DOI:10.1097/01.psy.0000208630.79271.a0
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- 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]
