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American Journal of Epidemiology Advance Access published online on February 8, 2006
American Journal of Epidemiology, doi:10.1093/aje/kwj092
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.
Received September 1, 2005
Accepted October 19, 2005

ORIGINAL CONTRIBUTIONS

Common Genetic Variation in the Prothrombin Gene, Hormone Therapy, and Incident Nonfatal Myocardial Infarction in Postmenopausal Women

Lucia A. Hindorff 1 *, Bruce M. Psaty 2, Christopher S. Carlson 3, Susan R. Heckbert 1, Thomas Lumley 4, Nicholas L. Smith 1, Rozenn N. Lemaitre 5, Mark J. Rieder 3, Deborah A. Nickerson 3, and Alexander P. Reiner 1

1 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA; Cardiovascular Health Research Unit, School of Medicine, University of Washington, Seattle, WA
2 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA; Cardiovascular Health Research Unit, School of Medicine, University of Washington, Seattle, WA; Department of Medicine, School of Medicine, University of Washington, Seattle, WA; Department of Health Services, School of Public Health, University of Washington, Seattle, WA
3 Department of Genome Sciences, School of Medicine, University of Washington, Seattle, WA
4 Cardiovascular Health Research Unit, School of Medicine, University of Washington, Seattle, WA; Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA
5 Cardiovascular Health Research Unit, School of Medicine, University of Washington, Seattle, WA

* To whom correspondence should be addressed.
Lucia A. Hindorff, E-mail: lah{at}u.washington.edu


  Abstract

Genetic variants in coagulation factors are associated with myocardial infarction and may modify the association between hormone therapy and cardiovascular disease risk. This study assessed whether common variation in the prothrombin gene was associated with incident nonfatal myocardial infarction in postmenopausal women and whether this association differed according to current estrogen use. Eight variants representing 98% of common prothrombin variants were selected using publicly available genomic variation data. These variants and the functional G20210A variant were genotyped and used to infer haplotypes in a population-based Washington State case-control study of postmenopausal Caucasian women (1995-1999; 273 cases and 788 controls). Women carrying a nonsynonymous polymorphism in exon 6 (C5467T) had an increased risk of myocardial infarction (for each additional copy, relative to women with one fewer copy, odds ratio = 1.4, 95% confidence interval: 1.0, 1.8). Prothrombin haplotypes were also associated with myocardial infarction (with minimal adjustment, global p = 0.056; with full adjustment, p = 0.034). Associations between haplotypes and myocardial infarction were similar among users of hormone therapy and nonusers (global p = 0.61), though statistical power was limited. These preliminary results suggest that common genetic variants in the prothrombin gene or other variants in linkage disequilibrium are associated with myocardial infarction in postmenopausal women.

Keywords: case-control studies; estrogen replacement therapy; female; genetics; myocardial infarction; polymorphism, genetic; postmenopause; prothrombin.
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