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Bezemer ID, Bare LA, Arellano AR, Reitsma PH, Rosendaal FR. Updated Analysis of Gene Variants Associated With Deep Vein Thrombosis. JAMA. 2010;303(5):421–422. doi:10.1001/jama.2010.57
To the Editor: A single-nucleotide polymorphism (SNP) association study1 assessing variants associated with deep vein thrombosis found that, of 19 682 gene-centric SNPs, 18 were consistently associated with deep vein thrombosis in the Leiden Thrombophilia Study (LETS) and in a subset of the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA-1). Nine of these SNPs were genotyped in the remaining part of the MEGA study (MEGA-2). Assays for the other 9 SNPs for MEGA-2 were not available at that time; the associations of these 9 SNPs with venous thrombosis in 1314 cases and 2877 controls of MEGA-2 were subsequently assessed.
Details of the study population, DNA collection, SNP selection, and genotyping were described previously.1 Chromosome 1 associations were stratified by factor V Leiden (rs6025, chr 1:167,785,673) to avoid reporting false-positive associations due to linkage disequilibrium. This analysis was previously performed for rs2227589 (SERPINC1 [NCBI Entrez Gene 462]) and rs670659 (RGS7 [NCBI Entrez Gene 6000]), which appeared to be independently associated.1 The SNPs rs6016 (chr 1:167,778,744), rs4524 (chr 1:167,778,379), rs3820059 (chr 1:167,657,778), and rs6131 (chr 1:167,847,509) were among the 9 SNPs pending genotyping in MEGA-2. The rs6016 SNP (F5 [NCBI Entrez Gene 2153]) was in linkage disequilibrium with rs4524 (F5, D" = 0.99 and r2 = 0.97 in LETS and MEGA-1), which has been reported to be associated with venous thrombosis.2 The SNP rs3820059 (C1orf114 [NCBI Entrez Gene 57821]) was in linkage disequilibrium with factor V Leiden (D" = 0.91 and r2 = 0.09) and not associated with venous thrombosis after adjustment for factor V Leiden in LETS and MEGA-1. The SNP rs6131 (SELP [NCBI Entrez Gene 6403]) was also not associated with venous thrombosis after adjustment for factor V Leiden, although linkage disequilibrium was not strong (D" = 0.34 and r2 = 0.03).
Six additional SNPs in MEGA-2 were genotyped: rs4524 (F5), rs1801690 (APOH [NCBI Entrez Gene 350]), rs3087546 (EPS8L2 [NCBI Entrez Gene 64787]), rs369328 (CASP8AP2 [NCBI Entrez Gene 9994]), rs881 (TACR1 [NCBI Entrez Gene 6869]), and rs2266911 (ODZ1 [NCBI Entrez Gene 10178]). The false discovery rates for the first 9 SNPs in MEGA-2 were previously reported.1 For the present analysis, the false discovery rate was manually recalculated for all 15 SNPs. Men and women were combined in all analyses including rs6048 (F9 [NCBI Entrez Gene 2158]) because the association with deep vein thrombosis in MEGA-2 was similar in men and women.3 Odds ratios, 95% confidence intervals, and P values were calculated by logistic regression using SPSS for Windows release 16.0.2 (SPSS Inc, Chicago, Illinois).
The associations between SNPs and deep vein thrombosis in MEGA-2 are presented in the Table. Of 6 newly genotyped SNPs, only rs4524 in F5 replicated in MEGA-2. The other SNPs had odds ratios close to 1 and corresponding P values >.20. After adjustment for factor V Leiden, rs4524 remained associated with venous thrombosis (odds ratio, 1.21; 95% confidence interval, 1.10-1.34). Linkage disequilibrium between factor V Leiden and rs4524 was low (r2 = 0.02 in MEGA-2).
The previous study1 identified 7 SNPs with a false discovery rate of less than 20%; 3 had P < .05 and a false discovery rate of less than 10% (rs13146272 in CYP4V2 [NCBI Entrez Gene 285440], rs2227589 in SERPINC1, and rs1613662 in GP6 [NCBI Entrez Gene 51206]). After recalculating the false discovery rate for 15 SNPs, 7 SNPs (including rs4524) had a false discovery rate of less than 20% (Table).
The rs4524 SNP in F5 was consistently associated with deep vein thrombosis in 3 large case-control studies. Five SNPs in APOH, EPS8L2, CASP8AP2, TACR1, and ODZ1 were associated in 2 case-control studies but failed to triplicate in the third study. The associations of 3 SNPs in F5, C1orf114, and SELP were due to linkage disequilibrium with other SNPs.
Author Contributions: Dr Rosendaal had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Bare, Reitsma, Rosendaal.
Acquisition of data: Bezemer, Bare.
Analysis and interpretation of data: Bezemer, Bare, Arellano, Reitsma.
Drafting of the manuscript: Bezemer.
Critical revision of the manuscript for important intellectual content: Bezemer, Bare, Arellano, Reitsma, Rosendaal.
Statistical analysis: Bezemer, Bare, Arellano.
Obtained funding: Rosendaal.
Administrative, technical, or material support: Bare, Arellano, Rosendaal.
Study supervision: Bare, Reitsma, Rosendaal.
Financial Disclosures: None reported.
Funding/Support: The Leiden Thrombophilia Study was supported by grant 89.063 from the Netherlands Heart Foundation. The Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis was supported by grant NHS 98.113 from the Netherlands Heart Foundation, grant RUL 99/1992 from the Dutch Cancer Foundation, and grant 912-03-0332003 from the Netherlands Organisation for Scientific Research. Celera reimbursed the Leiden University Medical Center for collecting, providing, and shipping the samples. Dr Bezemer received support for training in genetic epidemiology from the Leducq Foundation (Paris, France) for the development of Transatlantic Networks of Excellence in Cardiovascular Research (grant 04 CVD 02).
Role of the Sponsor: The funding organizations had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
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