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Psychosomatic Medicine 65:721-728 (2003)
© 2003 American Psychosomatic Society

ORIGINAL ARTICLES

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

Jeanne M. McCaffery, PhD, Maria Bleil, BA, Michael F. Pogue-Geile, PhD, Robert E. Ferrell, PhD and Stephen B. Manuck, PhD

From the Centers for Behavioral and Preventive Medicine, Brown Medical School and The Miriam Hospital (J.M.McC.), Providence, RI; Department of Psychology, University of Pittsburgh (M.B., M.F.P.-G., S.B.M.), Pittsburgh, PA; Department of Psychiatry, University of Pittsburgh Medical Center (M.F.P.-G., S.B.M.) Pittsburgh, PA; and Department of Human Genetics and Graduate School of Public Health, University of Pittsburgh (R.E.F.), Pittsburgh, PA.

Address reprint requests to: Jeanne McCaffery, PhD, Centers for Behavioral and Preventive Medicine, Coro Bldg., Suite 5000, One Hoppin Street, Providence, RI 02903. E-mail: Jeanne_McCaffery{at}brown.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 SUMMARY
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: To examine the effect of length variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) on individual differences in cardiovascular response to psychological challenge.

METHODS: Heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP) responses to computerized versions of two psychological challenges, the Stroop Color-Word Interference Test and mental arithmetic, were measured among 131 monozygotic (MZ) and 60 dizygotic (DZ) male or female (same-sex) European-American twin pairs. Among the 382 participants, 140 were homozygous for the "long" allele (l/l) at 5-HTTLPR, 61 were homozygous for the "short" allele (s/s), and 181 participants had one long and one short allele (l/s). Association and sib-pair analyses were performed to characterize genetic associations.

RESULTS: In the full sample, 5-HTTLPR was associated with HR reactivity to psychological challenge, albeit in interaction with sex. Task-elicited HR responses of women homozygous for the short allele were significantly greater than among: a) men of the same genotype; and b) women having either one (l/s) or two (l/l) long alleles at 5-HTTLPR. SBP and DBP responsivity was unrelated to genotype. These results were corroborated on reanalysis in two genetically independent subsamples. Variability at 5-HTTLPR also predicted HR reactivity in sib-pair analyses among DZ twins.

CONCLUSIONS: These results suggest that the commonly observed sex difference in HR reactivity may be, in part, genetically mediated and perhaps occur only among individuals homozygous for the short allele at 5-HTTLPR.

Key Words: genetics, • serotonin, • cardiovascular reactivity, • twins, • sex.

Abbreviations: 5-HIAA = 5-hydroxyindoleacetic acid;; 5HTT = Serotonin transporter gene;; 5HTTLPR = Serotonin transporter gene linked polymorphic region;; s = common allelic variant at 5HTTLPR labeled "short";; l = common allelic variant at 5HTTLPR labeled "long";; CNS = central nervous system;; CSF = cerebrospinal fluid;; DBP = diastolic blood pressure;; DZ = dizygotic;; HR = heart rate;; IBD = identity-by-descent;; MZ = monozygotic;; NTS = nucleus of the solitary tract;; SBP = systolic blood pressure;; SSRI = selective serotonin reuptake inhibitor;; ANOVA = analysis of variance;; SNK = Student Newman-Keuls post-hoc test.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 SUMMARY
 ACKNOWLEDGMENTS
 REFERENCES
 
It is widely hypothesized that a propensity to experience large elevations in heart rate and blood pressure under stress increases risk for cardiovascular disease. Recent investigations suggest, for instance, that exaggerated cardiovascular responses to standardized laboratory challenges may predict subsequent blood pressure elevation (1–7), preclinical atherosclerosis (8–10), cardiac ventricular enlargement (11, 12), and stroke (13, 14).

Twin studies demonstrate that genetic factors influence individual differences in heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP) responses to psychological challenge (15, 16) . Moderate to strong estimates of heritability (range 0.30–0.61) have been reported for HR reactivity, as elicited by cognitive stressors, such as the Stroop Color-Word Interference Test (17) and mental arithmetic (18–20). Blood pressure responses to the same tasks also appear to be heritable (range 0.20–0.80) (17, 19–22).

Williams (23) has suggested that reduced central nervous system (CNS) serotonergic activity may occasion a heightened physiological responsivity to psychological stress. Evidence for central serotonergic modulation of stress responsivity may be derived from both animal and human studies. In animal models, it has been shown that serotonin pathways innervate areas involved in cardiovascular regulation. Two major serotonin receptor subtypes, 5-HT1A and 5-HT2, 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). Homozygotes for the knockout (no copies of the 5-HTT gene) show no 5-HTT binding sites in different brain regions (brain stem, frontal cortex, hippocampus), whereas heterozygotes (one copy of the 5-HTT gene) show approximately 50% of the number of binding sites observed in controls (two copies of the 5-HTT gene) (26). Mice lacking both copies of the 5-HTT gene show a five-fold increase in extracellular 5-HT, as compared with control littermates (27). With regard to stress responsivity, these "knockout" mice also show nearly a four-fold greater increase in adrenocorticotropic hormone in response to the stress of injection than controls (28).

In humans, a role of serotonin in cardiovascular reactivity can be inferred from the effects of pharmacologic intervention with selective serotonin reuptake inhibitors (SSRIs). For example, treatment with citalopram reduced HR reactivity to a mental arithmetic challenge and urinary excretion of catecholamine among 60 healthy men (29), while paroxetine blunted SBP, DBP, HR, and plasma norepinephrine responses to a speech stressor in a pilot study of five men and women (30). Sertraline also decreased sympathetic activity among 12 healthy male and female participants (31).

To the extent that serotonin modulates sympathetic efferent activity in response to psychological stress, it is possible that genetic variation in components of the serotonergic system (eg, synthesis, reuptake, receptor activation) accounts for a portion of heritable individual differences in behaviorally induced cardiovascular reactivity (32). Of interest in the latter regard is a 44-base pair insertion/deletion polymorphism in the 5' regulatory region of the serotonin transporter (5-HTT) gene, located on chromosome 17. The common variation in the 5-HTT gene linked polymorphic region (5-HTTLPR) consists of two alleles, with repeats labeled "s" (short) and "l" (long). The "s" variant is associated with reduced transcriptional efficiency of the 5-HTT gene in in vitro assay systems, by comparison with the "l" allele (33, 34), as well as diminished serotonin (5-HT) uptake in platelets and cultured lymphoblasts (35). Reist et al. (36) have also demonstrated in vivo functionality of the 5-HTTLPR using a neuropharmacologic challenge to assess CNS serotonergic responsivity. In this latter investigation, men with at least one s allele showed blunted plasma prolactin responses to the 5-HT releasing agent, fenfluramine, compared with subjects homozygous for the l allele.

In a first report involving 54 healthy volunteers, Williams et al. (2001) (32) observed that cerebrospinal fluid (CSF) concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were lower among homozygotes for the s allele; HR and BP reactions to mental stress (affect recall tasks) were also reduced among s/s homozygotes. Relatedly, Williams et al. also found that subjects with lower CSF 5-HIAA levels exhibited smaller HR and BP responses than those with higher metabolite concentrations, although the genetic influence on reactivity appeared to be somewhat independent of variability in CSF 5-HIAA. In the present investigation, we further examine the effect of 5-HTTLPR variation on individual differences in cardiovascular response to psychological challenge, as seen in a genetically informed study design involving monozygotic and dizygotic (same sex) male and female twin pairs who participated in the Pittsburgh Twin Study.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 SUMMARY
 ACKNOWLEDGMENTS
 REFERENCES
 
Participants
Subjects were young adult twin pairs derived, as noted previously, from the Pittsburgh Twin Study, an investigation of genetic and environmental influences on cardiovascular and psychopathology risk factors and neuropsychological functioning (37–42). Recruitment methods have been described in detail previously (38). Exclusion criteria included: obesity (> 25% overweight by American Heart Association tables), diagnosis of hypertension, heart disease, cancer, kidney disease, or insulin-dependent diabetes, and use of any cardiovascular, psychotropic, or glucocorticoid medications or illicit drugs within 2 weeks before testing.

Of a total of 241 same-sex twin pairs who completed the study, genotyping of 5-HTTLPR was successful for 214 complete twin pairs. Missing genotypes were predominantly attributable to difficulty in maintaining venous access during the blood draw. Of the 214 twin pairs, 8 were not included in analyses due to incomplete cardiovascular data. To mitigate population stratification by ethnicity (43), individuals reporting ethnicities other than European-American were also excluded (African-Americans, 12 pairs; Asian-Americans, 2 pairs; other ethnicities (South American), 1 pair). This resulted in a total sample of 131 monozygotic (MZ) and 60 dizygotic (DZ) European-American twin pairs (382 individuals).

Cardiovascular Measures
As part of a larger battery of personality, psychophysiological, and neuropsychological measurements, participants performed two computer-based laboratory tasks, the Stroop Color-Word Interference Test and mental arithmetic, while HR, SBP, and DBP were monitored. The Stroop test, a cognitive interference task (44, 45), was presented for 6 minutes. Participants were instructed to identify the text color of a target word and select the name of the text color from four response choices. A computerized voice randomly announced color names to provide distraction and the time allotted to complete a given problem was titrated to the participant’s ability. During the mental arithmetic task, participants performed a series of challenging addition and subtraction problems for 6 minutes and task difficulty was again adjusted to yield comparable performance across subjects (38). Movement and verbal responding may confound the effects of the cognitive challenges on HR and blood pressure. Here, we minimized both by providing a microswitch, requiring the movement of fingers only, to respond to the tasks.

Each task was preceded by a 15-minute rest period. A minimally demanding color detection task was presented during the rest period to elicit an alert, unchallenged state and to reduce the effects of extraneous cognitive and motor activity (46). This "vanilla base-line" is conceptualized as a control period in which all of the experimental conditions are present except for the factor that elicits the response (psychological challenge) (47).

Heart rate data were collected during each task and the final 6 minutes of each rest period using electrocardiography. Blood pressure was obtained by automated oscillometric assessment (Dinamap Vital Signs Monitor, Model 8100, Critikon, Tampa, FL) at 90-second intervals during the last 6 minutes of the rest periods and throughout both tasks. Women participated during the follicular phase of their menstrual cycles and co-twins were generally tested within 1 week of each other.

DNA Extraction and Analysis
Blood samples were collected in 10 mM EDTA and DNA was isolated from lymphocytes using a salting out procedure (48). Zygosity determination by DNA fingerprinting in this sample has previously been described (38). Genotyping of 5-HTTLPR was achieved through polymerase chain reaction (PCR) amplification and visualization by gel electrophoresis (49). The 44 base pair deletion has been designated as the "s", or "short" variant, while the 44 base pair insertion has been designated the "l", or "long" variant. Thus, the three possible genotypes are "s/s" homozygotes, "l/s" heterozygotes, and "l/l" homozygotes.

Data Analysis
The electrocardiogram was digitalized and ensemble-averaged over 90-second periods; HR was calculated from the average interbeat interval. HR, SBP, and DBP were averaged across each rest and task period and reactivity for each cardiovascular parameter was expressed as the residual value resulting from regression of base-line measurements onto corresponding task change score for each response parameter.

To determine heritability of the cardiovascular parameters in the sample, twin structural equation modeling was performed for HR, SBP, and DBP responses averaged across the mental challenges. Twin structural equation modeling aims to explain the observed phenotypic variation (Var) and covariation (Cov) between MZ and DZ twins in terms of latent additive genetic (a2), shared environmental (c2), and nonshared environmental (e2) factors, such that Go


Thus, if the degree of similarity between MZ and DZ twins is proportional to their degree of genetic relatedness—MZ twins are more similar genetically than DZ twins by a factor of two—genetic variance is modeled as additive (a2). Additive genetic variance (a2) has been conceptualized as the combined effect of several genetic loci that are roughly equipotent regarding the phenotype of interest. Shared environment (c2) is defined as nongenetic factors that increase similarity among twins and is typically thought to reflect early rearing experiences such as parenting. Lastly, nonshared environment (e2) is defined as environmental factors that reduce similarity among twins, including measurement error. Model fit is assessed using a {chi}2 distribution with a nonsignificant {chi}2 reflecting good model fit. All models were estimated from variance/covariance matrices using the Mx program (51).

The extent to which 5-HTTLPR predicted cardiovascular response to psychological stress was first examined by repeated measures analysis of variance (ANOVA) in the full sample (N = 382 individuals). For these analyses, the mean change score for the HR, SBP, DBP response to each task was added back to the corresponding residuals to provide base-line-adjusted indices of reactivity for each task centered around the mean change in each parameter. The three genotypes at the 5-HTTLPR (s/s, l/s, and l/l) and sex were entered as between-subjects factors and task (Stroop and mental arithmetic) was entered as a within-subjects factor in the analysis of SBP, DBP, and HR responses to stress. In the event that variation at 5-HTTLPR was associated with a cardiovascular parameter in the full sample, we also conducted analyses in subsamples of genetically independent observations meeting the independent observation assumption of regression analysis (52). Here, we reconducted the repeated measures ANOVA using one and then the other twin, randomly selected (N = 191 for each sample), providing the opportunity for replication within one sample.

Lastly, we conducted sib-pair analyses, which eliminate potential biases due to population substructure (43). In ostensibly homogeneous samples, it is possible that subpopulations exist due to assortative mating or recent population admixture. Allele frequencies may differ between these subpopulations and, independently, so may the phenotype of interest, generating spurious association between genetic and phenotypic variation. Sib-pair analysis correlates within-pair differences in genotype and phenotype, allowing for a test of linkage among individuals from the same family and, thus, the same population. Here, we used the Haseman-Elston method (53), which tests for genetic linkage of a polymorphism with a given phenotype by examining the degree of variability among sib-pairs, as defined by the squared phenotypic difference between siblings, in relation to the number of alleles shared at a locus (eg, 0, 1, or 2 alleles shared among siblings at 5-HTTLPR). If the locus were linked to the phenotype, it would be expected that the squared trait differences between siblings would be related inversely to the number of shared alleles. Thus, more genotypic similarity would be associated with less phenotypic variability across the twin pair. As sib-pair analysis is based on allele sharing, this analysis was restricted to DZ twin pairs.

Of note, the Haseman-Elston method typically involves allele sharing identity-by-descent (IBD; the extent to which sib-pairs inherited alleles from a common ancestor) by siblings at a given locus. In this study, we were unable to confirm IBD status as we did not have access to parental genotypes and allele sharing was considered identity-by-state (the extent to which sib-pairs share alleles without regard to ancestry; influenced by inheritance and genotype frequency in the population). Thus, the sib-pair analyses presented here may be somewhat less powerful than the Haseman-Elston method incorporating allele-sharing IBD.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 SUMMARY
 ACKNOWLEDGMENTS
 REFERENCES
 
Descriptive Statistics
Participants had a mean age of 21 years (SD = 2.78) and had completed an average of 13.9 years of schooling (SD = 1.76); 50% were female. The means and standard deviations for HR (in beats per minute), SBP, and DBP (in mm Hg) at rest were 75.4 (10.8), 114.2 (9.8), and 60.8 (6.8), respectively. With regard to task-elicited cardiovascular reactivity, the Stroop task was associated with a mean increase in HR, SBP, and DBP of +8.9 (7.8), +10.2 (6.5), and +6.7 (5.0), respectively. Task changes differed significantly from base-line values in each instance (p values < .001). Somewhat smaller average task levels were observed during mental arithmetic for HR (+5.6 (6.2)), SBP (+6.9 (5.8)), and DBP (+5.0 (4.7)), although these changes were also highly significant (p values < .001). Average changes in HR, SBP, and DBP observed here are comparable to responses seen in previous studies using the Stroop task (54–57) and mental arithmetic (56–60). Means and variances of HR, SBP, and DBP responsivity did not differ across MZ and DZ twins (p values > .10).

One hundred forty participants (66 male and 74 female) were homozygous for the long allele (l/l), 181 (102 male, 74 female) were heterozygous (l/s), and 61 (24 male and 37 female) were homozygous for the short allele (s/s) at 5-HTTLPR, yielding allele frequencies of 0.60 for the l allele and 0.40 for the s allele. The distribution of l and s alleles conformed to the Hardy-Weinberg equilibrium ({chi}2 (2)= 0.03, p > .50).

Twin Structural Equation Modeling
Twin structural equation models were first fit separately for males and females and it was determined whether model parameters could be equated across gender. Equating parameter estimates did not compromise model fit significantly for SBP or DBP reactivity (p values > .10), suggesting no difference in these parameter estimates according to gender. For HR reactivity, the model results tended to differ across sex, although the interaction did not reach statistical significance (.05 < p < .10).

As parameter estimates did not differ significantly by sex, twin analyses were performed with parameters constrained across males and females. Univariate twin structural equation model estimates are listed in Table 1. HR, SBP, and DBP responses were each significantly heritable (p values<=0.05), with an additional contribution of nonshared environment. There was no evidence for a shared environmental contribution to any of the response parameters (p values > .10). Model fits were acceptable for SBP and DBP reactivity, although not as good for HR reactivity, likely due to a marginal interaction with sex.


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  		TABLE 1. Univariate twin structural equation modeling parameter estimates for cardiovascular reactivity across men and women
 
Association Analyses
Heart Rate Reactivity
The analysis of HR reactivity in the full sample showed significant between-subjects main effects of genotype (F(2,376) = 5.24, p < .01) and sex (F(1,376)= 28.86, p < .001), as well as a significant genotype x sex interaction (F(2,376)=10.67, p < .001). In within-subjects analyses, the Stroop task evoked larger HR responses than mental arithmetic (F(1,376) = 122.01, p < .001), but no task-dependent interactions were found to be significant.

Sex and genotype effects on HR reactivity are depicted in Figure 1A. Females showed greater HR reactivity than males, but no significant difference in HR reactivity as a function of genotype was detected in post-hoc analysis (Student-Newman-Keuls (SNK) test: p values > .05). With regard to the genotype x sex interaction, females who were homozygous for the s allele had a significantly larger HR response than males of the same genotype (females: mean = +13.0, SD = 7.0, males: mean = +3.8, SD = 5.6; SNK, p < .01) and greater HR responses than women of either l/s (s/s: mean = +13.0, SD = 7.0, l/s: mean = +6.9, SD = 5.9; SNK, p < .05) or l/l genotype (s/s: mean = +13.0, SD = 7.0, l/l: mean = +7.8, SD = 6.4; SNK, p values < .05). HR responses did not vary by genotype among males (SNK, p values > .10).



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  		Fig. 1. Mean (± standard error) heart rate reactivity across task by genotype at 5-HTTLPR among men and women. (A) Full sample (N = 382). (B) Genetically independent sample 1 (N = 191). (C) Genetically independent sample 2 (N = 191).

 
As variation at 5-HTTLPR predicted HR responses in relation to sex in the full sample, analyses of genetically independent subsamples and sib-pair analyses were pursued. For the genetically independent subsamples, members of each twin pair were randomly assigned to two different groups (N's = 191) and association analyses for HR reactivity were performed within these groups. For the first group (Fig. 1B), a two-way repeated measures ANOVA revealed a significant within-subjects effect for task (F(1,185)= 50.14, p < .001), a significant between-subjects effect for sex (F(1,185)= 4.94, p < .03), and a significant genotype x sex interaction (F(2,185)=3.08, p < 0.05). In the second group (Fig. 1C), the significant task (F(1,185)= 69.24, p < .001), sex (F(1,185)= 6.13, p < .01), and genotype x sex (F(2,185)= 7.66, p = .001) effects also emerged, with an additional significant main effect of genotype (F(2,185)= 6.12, p < .01).

Direction of the main effects for task and sex was consistent across the groups and with analyses in the full sample. Similar, too, was the nature of the interaction between sex and genotype, although post-hoc tests only reached statistical significance in the second group. Specifically, within the second group, females who were homozygous for the s allele had significantly larger HR response than males of the same genotype (females: mean = +14.9, SD = 6.8, males: mean = +3.5, SD = 5.6; SNK, p < .01) and greater HR responses than women having either l/s (s/s: mean = +14.9, SD = 6.8, l/s: mean = +6.7, SD = 5.9; SNK, p < .01) or l/l genotype (s/s: mean = +14.9, SD = 6.8, l/l: +9.0, SD = 6.3; SNK, p < .01). No other significant differences between groups were observed (SNK, p values > .10).

Overall, results seen in the full sample were closely corroborated on analysis of the two genetically independent subsamples. Females exhibited heightened HR reactivity, relative to males, and the Stroop task elicited larger increases in HR than did mental arithmetic. Some evidence for a main effect of genotype was provided in the full sample and second subsample; however, effects of genotype were qualified by a genotype x sex interaction in each of these analyses. s/s homozygous women experienced greater HR reactions across the two tasks as compared with men of the same genotype and to women carrying at least one l allele (l/s or l/l genotypes).

To examine within-family effects, the degree to which allele sharing at 5-HTTLPR was associated with variability among siblings in HR reactivity (as indexed by squared sibling differences) was tested in DZ twin pairs (N = 60). Due to the small number of twin pairs who shared no alleles (N = 2), this group was combined with pairs sharing one allele (N = 21). Thus, the between-subjects variable in this analysis contrasted twin pairs who shared zero or one alleles (N = 23) with pairs sharing two alleles (N = 37). Squared sibling differences in HR reactivity as a function of allele sharing at 5-HTTLPR are depicted in Figure 2.



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  		Fig. 2. Mean (± standard error) squared sibling differences in HR reactivity across task by degree of allele sharing at 5-HTTLPR (N = 60 sib-pairs).

 
Main effects of task (F(1,56)= 15.02, p < .001), sex (F(1,56) = 5.74, p= .02) and allele sharing (F(1,56)= 4.15, p < .05) on the squared difference in HR response between siblings were observed. These results suggest that the Stroop task and female sex were associated with more variability among siblings, as compared with the math task and male sex, respectively. In addition, a greater degree of allele sharing at 5-HTTLPR was associated with less between-sibling variability in HR reactivity, indicating that siblings who were more similar genetically (shared more alleles) at this locus were also more similar in their HR reactivity (less intra-pair variability) than siblings who were less similar in genotype (shared fewer alleles) at this site. Although the allele sharing x sex interaction did not reach statistical significance (p = .18), it is clear from Figure 2 that the main effect of allele sharing is driven by greater variability in HR reactivity among female sib-pairs who share zero or one alleles at 5-HTTLPR, relative to their female counterparts sharing both alleles at this locus.

That sibling-pair differences in allele sharing at 5-HTTLPR predicted phenotypic variability in HR reactivity indicates genetic linkage of 5-HTTLPR with HR reactivity in this sample, albeit predominantly among women. Because the relationships were observed within families (here, sib-pairs), these results are resistant to confounding by population stratification.

Systolic and diastolic blood pressure reactivity
In the full sample, SBP and DBP differed significantly across tasks (F values (1, 370) > 43.00, p values < .001), reflecting greater blood pressure responses to the Stroop task than mental arithmetic. 5-HTTLPR did not predict SBP or DBP responses to these stressors (F values (2, 370) < 2.00, p values > 0.10), nor did sex (F values (2) < 0.50, p values > 0.50). One task x 5-HTTLPR interaction did emerge (F(2,370)= 3.16, p = .04), suggesting that individuals of l/s and s/s genotype showed higher DBP response to the Stroop task than to mental arithmetic (l/s, Stroop: mean = +6.73, SD = 5.03, math: mean = +4.60, SD = 4.78, p < .05; s/s, Stroop: mean = 7.07, SD = 5.15, math: mean = 5.10, SD = 4.88; p < .05), whereas individuals of l/l genotype did not (l/l, Stroop: mean = 6.34, SD = 4.99, math: mean = 5.44, SD = 4.73, p > .05). No other post-hoc comparisons approached statistical significance within this interaction (p values > .05) and no other interactions approached statistical significance in the ANOVA, including the sex x 5-HTTLPR interaction (p values > .10).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
SUMMARY
 ACKNOWLEDGMENTS
 REFERENCES
 
This investigation aimed to further examine the effects of common variation in the promoter region of the serotonin transporter gene (5-HTTLPR) on individual differences in behaviorally evoked cardiovascular reactivity. Our results show the 5-HTTLPR to be associated with HR reactivity, albeit only in interaction with sex. Females of s/s genotype exhibited substantially larger HR responses to our psychological challenges than did males of the same genotype, and larger HR reactions than their female counterparts having one or two long alleles. These results suggest that the sex differences in HR reactivity, which were observed in this study and are also well established in prior literature (57, 60–63), may be influenced by variation of a bi-allelic repeat polymorphism in the regulatory region of the gene encoding the serotonin transporter.

Twin Structural Equation Modeling
Before molecular genetic analyses, a quantitative genetic analysis was first performed to determine the extent to which heart rate and blood pressure reactivity are heritable in this sample of young adult twins. Results were largely consistent with those reported previously on a somewhat different sample (38). Across men and women, HR, SBP, and DBP responses to the psychological challenges were each significantly heritable and influenced by nonshared environmental effects. There was no evidence of a shared environmental influence on any of the cardiovascular response parameters.

Nonetheless, it should be noted that, although not statistically significant, a trend for an interaction with sex was observed in twin modeling, as reflected by a marginal increase in {chi}2 when the genetic (a2), shared environmental (c2), and nonshared environmental (e2) parameters were constrained across men and women (p < .10). This trend toward interaction was also likely reflected in the poor fit of the a2 + c2 + e2 model to the HR reactivity data (p = .01). When examined within sex, HR reactivity appeared more heritable among females than males (data not shown). To the extent that that the s allele at 5-HTTLPR increases genetic variance (heritability) in HR reactivity largely among women, the marginal gene x sex interaction observed in twin modeling would be consistent with greater effects of 5HTTLPR on HR reactivity among women.

Association Analyses
Overall, HR, SBP, and DBP reactivity were substantially higher during the Stroop than the mental arithmetic task. In addition, we replicated an observation reported frequently in the literature, namely that women exhibit higher HR reactivity than men (57, 60–63) . Furthermore, there was a main effect of 5-HTTLPR on HR reactivity, but this association was qualified consistently with a gene x sex interaction.

With respect to the interaction of sex and genotype, females homozygous for the s allele exhibited elevated HR reactivity relative to males of the same genotype and to women carrying at least one l allele. On the other hand, no sex differences were observed among l/s and l/l genotypes in any of the samples, nor were differences between males of differing genotype observed.

It is important to note that the interactive influences of genotype and sex on subjects’ HR responses obtained not only in the full sample but also in each of two genetically independent subsamples; hence, these effects were not an artifact of the statistical non-independence of participants in the full sample (due to the genetic relatedness of MZ and DZ twins). The two genetically independent subsamples also permitted internal replication of findings.

The sex x 5-HTTLPR interaction also tended to persist on more conservative analysis resistant to the potential confounding by population substructure (43). Population substructure can yield a spurious genetic association caused by differences in allele frequency and a phenotype of interest in subgroups within a larger population. For example, it has been observed previously that African Americans respond to psychological challenge with a more "vascular" pattern of cardiovascular reactivity than Caucasian Americans. In a study collapsing across ethnicity, every allele that differs in frequency between African Americans and Caucasian Americans will appear to be associated with vascular reactivity despite the likely causal relevance of only a few alleles.

Family designs, such as sib-pair analyses, serve as one method to guard against this potential for "false-positive" results, as comparisons are conducted within families and thus do not contrast individuals from different population subgroups. In sib-pair analyses in this sample, DZ twin pairs who shared two alleles at 5-HTTLPR showed a greater degree of similarity in HR reactivity (less intra-pair variability) than DZ twin pairs who shared 0 or 1 allele at this locus. This result indicates genetic linkage of this serotonin transporter locus with HR reactivity. The allele sharing x sex interaction did not reach statistical significance, likely due to the limited power to detect associations in sib-pair analyses with small sample sizes (64, 65). Nonetheless, it was clear that allele sharing at this locus was most strongly associated with HR reactivity among women—a similar pattern of gene x sex interaction as observed in association analyses, which have greater statistical power.

The results of the present study differ from the one prior investigation examining the association of 5-HTTLPR with cardiovascular reactivity (32). Comparing s/s homozygotes against l/s and l/l genotypes, Williams et al. (32) found s/s participants to have lower reactivity of HR and mean arterial pressure, whereas we find HR reactivity to be elevated among s/s homozygotes, and only among females of this genotype. Differences in sample characteristics between the studies may resolve some of the apparent discrepancy. The Williams study was a first report based on 54 unrelated participants, ages 18 to 49, 54% white, 46% black and 67% male. The present study reports on a larger, family-based sample –191 twin pairs, ages 18 to 30 –permitting estimation of phenotypic heritability and within family genetic linkage. In addition, approximately half of the present sample was female, increasing the power to detect gene x sex interaction. Nonetheless, it should be noted that, although not significant statistically, the pattern of association among men was consistent with that found in the Williams et al. study.

Important for reducing the likelihood of a "false-positive" in genetic association analyses, the present study also limited ethnic variation by excluding the few participants reporting ethnicities other than European-American (8%) to mitigate population stratification; this precaution was not taken in the Williams et al. study. The lack of adequate sample size to examine genetic associations within ethnic groups other than European-Americans is, nonetheless, a limitation of the present study. The nature of the psychological challenges, in this study primarily cognitive tasks and in the Williams et al. study an anger and sadness elicitation protocol, may have also contributed to differences in outcome. Although of somewhat different outcome than Williams et al., the present study extends prior observations by showing cardiac reactivity to vary with respect to polymorphic variation at the 5-HTT locus and to do so variably by sex.

Possible Mechanisms
The mechanisms by which variability at 5-HTTLPR may be associated with behaviorally evoked HR reactivity are likely to be complex. For example, the putative functional significance of 5-HTTLPR variation appears inconsistent with the studies of CNS serotonin turnover and responsivity. In in vitro studies of functionality (33–35), the s allele at 5-HTTLPR was associated with reduced transcriptional efficiency of the gene that codes for the serotonin transporter, resulting in fewer serotonin re-uptake sites and more synaptic availability of serotonin. However, in vivo studies suggest that the s allele is associated with reduced CNS serotonergic responsivity, as indexed by diminished prolactin responses to serotonin-releasing agent, fenfluramine (36), and possibly reduced serotonin turnover, as estimated by the CSF concentration of the serotonin metabolite, 5-HIAA (32). Williams et al. (32) hypothesized that the apparent contradiction between fewer re-uptake sites and lower serotonin turnover may result from reduced stimulation of presynaptic 5-HT1a autoreceptors among individuals having genotypes containing the l allele. As the 5-HT1a receptor exerts negative feedback on serotonin release, reduced stimulation of these receptors may ultimately yield a net increase in serotonergic neurotransmission.

Evidence of the effects of CNS serotonergic activity on cardiovascular function is also complex. As mentioned previously, two 5-HT receptors produce opposing effects on sympathetic activity. Central microinjections of 5-HT1a receptor agonists into the forebrain produce dose-dependent decreases in HR and blood pressure in laboratory rats (66), whereas stimulation of 5-HT2 receptors causes a dose-dependent increase in HR and blood pressure (67). It should also be noted that acute effects of serotonergic stimulation on cardiovascular function do not necessarily reflect the effects of basal serotonergic "tone" on HR, BP, or cardiovascular reactivity to challenge (68). Despite the intricacy, it is clear that central serotonergic activity plays a prominent role in sympathetic activity and stress response.

Finally, with regard to the sex x 5-HTTLPR interaction, one study by Pecins-Thompson et al. (69) suggests that expression of the serotonin transporter gene is influenced by the reproductive hormones, estrogen and progesterone. In this study, treatment of ovarectomized rhesus monkeys with estrogen, or estrogen plus progesterone, reduced serotonin transporter mRNA expression in the dorsal and median raphe by approximately 33%, compared with untreated animals. In a second study (70), treatment with estrogen augmented SBP responsivity to serotonergic challenge among hypophysectomized female rats, as compared with untreated controls. Given the apparent effect of estrogen on the expression of the serotonin transporter gene and on vascular responsivity in the presence of serotonin, it is possible that estrogen interacts with genetic variation at 5-HTTLPR to account, in part, for the sex-limited effects in the present study.


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 SUMMARY
ACKNOWLEDGMENTS
 REFERENCES
 
In summary, this study aimed to further characterize effects of polymorphic variability associated with the 5-HTT gene on cardiovascular reactivity to stress. Our results showed genotype and sex to interact substantially in the prediction of HR reactivity. Females homozygous for the s allele at 5-HTTLPR exhibited exaggerated HR responses relative to males of the same genotype and to females carrying at least one l allele. SBP and DBP responsivity, on the other hand, did not differ by 5-HTTLPR genotype. Overall, these results support the hypothesis that central serotonergic function influences HR reactivity, particularly among women, and suggest that variability at this regulatory locus in the serotonin transporter gene may contribute to well-established sex differences in HR reactivity.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 SUMMARY
 ACKNOWLEDGMENTS
REFERENCES
 
Preparation of this article was supported by Grants HL-40962 and U-10 HL54526.

Received for publication August 30, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 SUMMARY
 ACKNOWLEDGMENTS
 REFERENCES
 

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