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Original Articles

An Evaluation of Candidate Genes of Inflammation and Thrombosis in Relation to the Risk of Venous Thromboembolism

The Women’s Genome Health Study

Robert Y.L. Zee, PhD; Robert J. Glynn, PhD; Suzanne Cheng, PhD; Lori Steiner, BS; Lynda Rose, MS and Paul M Ridker, MD

From the Division of Preventive Medicine (R.Y.L.Z., R.J.G., L.R., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and Roche Molecular Systems, Inc (S.C., L.S.), Pleasanton, Calif.

Correspondence to Robert Y.L. Zee, BDS, MPH, PhD, Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215. E-mail rzee{at}rics.bwh.harvard.edu

Received June 25, 2008; accepted December 3, 2008.

Background— Although pathways associated with hemostasis and thrombosis are well documented to have an impact on venous thromboembolism (VTE), whether the inflammatory cascade also influences VTE risk is uncertain.

Methods and Results— We evaluated 51 polymorphisms from 32 inflammation-related genes (and an additional 19 polymorphisms from 15 thrombosis-related genes) as potential determinants of VTE in a prospective cohort of 22 413 white women followed over a 10-year period. Hazard ratios (HRs) for incident VTE according to the different genotypes were assessed by Cox proportional-hazards models. The false discovery rate (FDR) was used for correction for multiple testing with a 0.20 cut point. During follow-up, 158 idiopathic and 180 secondary VTE events occurred. As anticipated, factor V Leiden (HR, 3.22; 95% CI, 1.92 to 5.40; P<0.0001; FDR=0.004) and the prothrombin mutation (HR, 2.57; 95% CI, 1.64 to 4.02; P<0.0001; FDR=0.004) were both strongly associated with incident idiopathic VTE, as was the rs6046 polymorphism in the factor VII gene (HR, 0.54; 95% CI, 0.35 to 0.86; P=0.008; FDR, 0.12). With regard to polymorphism in the inflammatory genes, variation at rs1143634 in the IL-1β gene was associated with a reduced risk of idiopathic VTE (HR, 0.59; 95% CI, 0.44 to 0.80; P=0.0007; FDR=0.02), whereas variation at rs1800872 in the IL-10 gene was associated with increased risk (HR, 1.42; 95% CI, 1.12 to 1.80; P=0.004; FDR=0.07). By contrast, no significant associations were found for secondary VTE events.

Conclusion— In addition to previously reported polymorphisms associated with hemostasis and thrombosis, these prospective cohort data suggest that genetic variation in IL-1 β and IL-10 genes may also influence the risk of idiopathic VTE.

Key Words: genetics • VTE • polymorphisms • candidate genes • risk factors

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CLINICAL PERSPECTIVE

Guest editor for this article was Teri A. Manolio, MD, PhD.

The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.108.801969/DC1.

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An Evaluation of Candidate Genes of Inflammation and Thrombosis in Relation to the Risk of Venous Thromboembolism: The Women’s Genome Health Study

Robert Y.L. Zee, Robert J. Glynn, Suzanne Cheng, Lori Steiner, Lynda Rose, and Paul M Ridker
Circ Cardiovasc Genet 2009 2: 57-62. [Abstract] [Full Text] [PDF]