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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

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

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.

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