Published Online
on May 1, 2006

A more recent version of this article appeared on May 9, 2006

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Submitted on January 19, 2006
Revised on March 8, 2006
Accepted on March 10, 2006

Polymorphism in the ₂-Adrenergic Receptor and Lipoprotein Lipase Genes as Risk Determinants for Idiopathic Venous Thromboembolism. A Multilocus, Population-Based, Prospective Genetic Analysis

Robert Y.L. Zee PhD^*, Nancy R. Cook ScD, Suzanne Cheng PhD, Henry A. Erlich PhD, Klaus Lindpaintner MD, and Paul M Ridker MD

From the Center for Cardiovascular Disease Prevention, Leducq Center for Molecular and Genetic Epidemiology, and Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (R.Y.L.Z., N.R.C., P.M.R.); Department of Human Genetics, Roche Molecular Systems, Alameda, Calif (S.C., H.A.E.); and Roche Center for Medical Genomics, Basel, Switzerland (K.L.).

^* To whom correspondence should be addressed. E-mail: rzee{at}rics.bwh.harvard.edu.

Background--Candidate genes in inflammation, thrombosis, coagulation, and lipid metabolism pathways have been implicated in venous thromboembolism (VTE).

Methods and Results--Using DNA samples collected at baseline in the Physicians’ Health Study cohort, we genotyped 92 polymorphisms from 56 candidate genes among 304 individuals who subsequently developed VTE (144 idiopathic, 156 secondary cases) and among 2070 individuals who remained free of reported vascular disease over a mean follow-up of 13.2 years to prospectively determine whether these gene polymorphisms contribute to the risk of VTE. For idiopathic VTE, in addition to the factor V (Leiden) mutation (odds ratio [OR], 5.13; 95% confidence interval [CI], 3.24 to 8.14; P<0.0001; false discovery rate [FDR], P<0.0001), an N291S lipoprotein lipase gene polymorphism (OR, 3.09; 95% CI, 1.56 to 6.09; P=0.001; FDR, P=0.036) and a Q27E ₂-adrenergic receptor gene polymorphism (OR, 1.40; 95% CI, 1.09 to 1.79; P=0.006; FDR, P=0.036) were found to be significantly associated with increased risk. For secondary VTE, a Q360H apolipoprotein A4 gene polymorphism (OR, 0.34; 95% CI, 0.18 to 0.65; P=0.001; FDR, P=0.07) and an I50V interleukin-4 receptor polymorphism (OR, 0.66; 95% CI, 0.52 to 0.84; P=0.0009; FDR, P=0.07) were moderately, but not statistically and significantly, associated with reduced risk after adjustment for multiple comparisons.

Conclusions-These present findings are hypothesis generating and require replication and confirmation in an independent investigation.

Key words: genetics • multilocus • polymorphisms • risk factors • venous thromboembolism

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