on April 13, 2006
Published online before print April 13, 2006, doi: 10.1161/01.ATV.0000222011.13026.25
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Submitted on November 28, 2005
Accepted on March 17, 2006
Common Genetic Variation in Five Thrombosis Genes and Relations to Plasma Hemostatic Protein Level and Cardiovascular Disease Risk
Sekar Kathiresan ;
From the National Heart, Lung, and Blood Institute Framingham Heart Study (S.K., M.G.L., C.J.O.), Framingham, Mass; Broad Institute of Harvard University and Massachusetts Institute of Technology (S.K., S.B.G., A.L.C., J.N.H., C.J.O.), Cambridge; Department of Biostatistics (Q.Y.), Boston University School of Public Health, Department of Neurology (Q.Y.), Boston University School of Medicine, Department of Mathematics and Statistics (M.G.L.), Boston University, Massachusetts; Royal North Shore Hospital (G.H.T.), Sydney, Australia; Divisions of Genetics and Endocrinology (J.N.H.), Children’s Hospital and Department of Genetics, Harvard Medical School, Boston, Mass; and Cardiology Division (S.K., C.J.O.), Massachusetts General Hospital, Harvard Medical School, Boston.
* To whom correspondence should be addressed. E-mail: odonnellc{at}nhlbi.nih.gov.
Objective--We undertook a linkage disequilibrium (LD)-based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD).
Methods and Results--In a reference panel, we characterized LD structure at the fibrinogen gene cluster (fibrinogen-
[FGB], FGA, and FGG), factor VII (F7), and tissue plasminogen activator (PLAT) loci. Forty-one tag single nucleotide polymorphisms (SNPs) were genotyped in 1811 unrelated Framingham Heart Study participants. There were significant associations of 9 FGB SNPs with fibrinogen level (minimum P=0.002) and of 7 F7 SNPs and F7 level (minimum P<0.0001). SNPs at the PLAT locus were not associated with PLAT level. In stepwise analysis, a single FGB variant explained 1% of the residual variance in fibrinogen level, and 2 F7 SNPs together explained 10% of the residual variance in F7 level. Two PLAT haplotypes were associated with CVD (multivariable-adjusted global P=0.0004).
Conclusions--A comprehensive survey of common sequence variation demonstrates that cis-regulatory SNPs explain a modest proportion of the residual variance in circulating fibrinogen and F7 level and PLAT haplotypes increase the risk of CVD. Additional studies are warranted to confirm the association of PLAT sequence, variation, and risk of CVD. We hypothesized that cis-acting SNPs influence hemostatic protein levels or CVD risk. In Framingham Heart Study participants, a single FGB SNP explained 1% of fibrinogen level variance, and 2 F7 SNPs together explained 10% of F7 level variance. PLAT gene haplotypes were associated with CVD.
Key words: coagulation • fibrinogen • genetics • myocardial infarction • plasminogen activators • thrombosis • polymorphism
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