Gene variants associated with deep vein thrombosis

被引:240
作者
Bezemer, Irene D. [1 ]
Bare, Lance A. [4 ]
Doggen, Carine J. M. [1 ]
Arellano, Andre R. [4 ]
Tong, Carmen [4 ]
Rowland, Charles M. [4 ]
Catanese, Joseph [4 ]
Young, Bradford A. [4 ]
Reitsma, Pieter H. [2 ,3 ]
Devlin, James J. [4 ]
Rosendaal, Frits R. [1 ,2 ,3 ]
机构
[1] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RC Leiden, Netherlands
[2] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, NL-2300 RC Leiden, Netherlands
[3] Leiden Univ, Med Ctr, Dept Thrombosis & Hemostasis, NL-2300 RC Leiden, Netherlands
[4] Celera, Alameda, CA USA
来源
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION | 2008年 / 299卷 / 11期
关键词
D O I
10.1001/jama.299.11.1306
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Context The genetic causes of deep vein thrombosis ( DVT) are not fully understood. Objective To identify single- nucleotide polymorphisms ( SNPs) associated with DVT. Design, Setting, and Patients We used 3 case- control studies of first DVT. A total of 19 682 gene- centric SNPs were genotyped in 443 cases and 453 controls from the Leiden Thrombophilia Study ( LETS, 1988- 1992). Twelve hundred six SNPs associated with DVT were reinvestigated in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis study ( MEGA- 1, 1999- 2004) in a subset of 1398 cases and 1757 controls. Nine SNPs associated with DVT in both LETS and MEGA- 1 were investigated a third time in 1314 cases and 2877 controls from MEGA- 2, a second subset of MEGA. Additional SNPs close to one SNP in CYP4V2 were genotyped in LETS and MEGA- 1. Main Outcome Measure Odds ratios ( ORs) for DVT were estimated by logistic regression. False discovery rates served to investigate the effect of multiple hypothesis testing. Results Of 9 SNPs genotyped in MEGA- 2, 3 were strongly associated with DVT ( P <. 05; false discovery rate <=. 10): rs13146272 in CYP4V2 ( risk allele frequency, 0.64), rs2227589 in SERPINC1 ( risk allele frequency, 0.10), and rs1613662 in GP6 ( risk allele frequency, 0.84). The OR for DVT per risk allele was 1.24 ( 95% confidence interval [ 95% CI], 1.11- 1.37) for rs13146272, 1.29 ( 95% CI, 1.10- 1.49) for rs2227589, and 1.15 ( 95% CI, 1.01- 1.30) for rs1613662. In the region of CYP4V2, we identified 4 additional SNPs ( in CYP4V2, KLKB1, and F11) that were also associated with both DVT ( highest OR per risk allele, 1.39; 95% CI, 1.11- 1.74) and coagulation factor XI level ( highest increase per risk allele, 8%; 95% CI, 5%- 11%). Conclusions We identified SNPs in several genes that were associated with DVT. We also found SNPs in the region around the SNP in CYP4V2 ( rs13146272) that were associated with both DVT and factor XI levels. These results show that common genetic variation plays an important role in determining thrombotic risk.
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收藏
页码:1306 / 1314
页数:9
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