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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-07-2308.
Submitted July 30, 2002
Accepted November 19, 2002
Genetic variants of coagulation factor XIII, post-menopausal estrogen therapy, and risk of non-fatal myocardial infarction
Alexander P Reiner*, Susan H Heckbert, Hans L Vos, Robert A Ariens, Rozenn N Lemaitre, Nicholas L Smith, Thomas Lumley, Thomas D Rea, Lucia A Hindorff, Gina D Schellenbaum, Frits R Rosendaal, David S Siscovick, and Bruce M Psaty
Epidemiology, University of Washington, Seattle, WA, USA
Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Molecular Vascular Medicine, University of Leeds, Leeds, United Kingdom
Biostatistics, University of Washington, Seattle, WA, USA
Medicine, University of Washington, Seattle, WA, USA
Medicine, University of Washington, Seattle, WA, USA; Epidemiology, University of Washington, Seattle, WA, USA
Medicine, University of Washington, Seattle, WA, USA; Epidemiology, University of Washington, Seattle, WA, USA; Molecular Vascular Medicine, University of Leeds, Leeds, United Kingdom
* Corresponding author; email: apreiner{at}u.washington.edu.
We hypothesized that possession of either of two functional coagulation factor XIII polymorphisms, one within subunit A (Val34Leu) and one within subunit B (His95Arg), might modulate the prothrombotic effects of estrogen and help to explain the variation in incidence of arterial thrombotic events among post-menopausal women using hormone replacement therapy. In a population-based case-control study of 955 post-menopausal women, we assessed the associations of factor XIII genotypes and their interactions with estrogen therapy on risk of non-fatal myocardial infarction (MI). The presence of the factor XIIIA Leu34 allele was associated with a reduced risk of MI [odds ratio (OR)=0.70, 95% confidence interval (95%CI)=0.51-0.95]. The presence of the factor XIIIB Arg95 allele had little association with MI risk. Neither factor XIII polymorphism alone significantly modified the association between the risk of MI and current estrogen use. In exploratory analyses, however, there was a significant factor XIII subunit gene-gene interaction. Compared to women homozygous for both common factor XIII alleles, the Arg95 variant was associated with a reduced risk of MI in the presence of the Leu34 variant (OR=0.36, 95%CI=0.17-0.75) but not in the absence of the Leu34 variant (OR=1.11, 95%CI=0.69-1.79). Moreover, among women who had 2 or more copies of the variant factor XIII alleles and were current estrogen users, the risk of MI was reduced by 70% relative to estrogen non-users with <2 factor XIII variant alleles (P-value for interaction=0.03). If confirmed, these findings may permit a better assessment of the cardiovascular risks and benefits associated with postmenopausal estrogen therapy.
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