Genome-wide linkage scan in affected sibling pairs identifies novel susceptibility region for venous thromboembolism: Genetics In Familial Thrombosis study

被引:20
作者
de Visser, M. C. H. [1 ]
van Minkelen, R. [1 ]
van Marion, V. [1 ]
den Heijer, M. [2 ,3 ]
Eikenboom, J. [1 ]
Vos, H. L. [1 ]
Slagboom, P. E. [4 ]
Houwing-Duistermaat, J. J. [5 ]
Rosendaal, F. R. [1 ,3 ]
Bertina, R. M. [1 ]
机构
[1] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Dept Thrombosis & Hemostasis, NL-2300 RC Leiden, Netherlands
[2] Vrije Univ Amsterdam, Dept Endocrinol, Med Ctr, Amsterdam, Netherlands
[3] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RC Leiden, Netherlands
[4] Leiden Univ, Med Ctr, Dept Mol Epidemiol, NL-2300 RC Leiden, Netherlands
[5] Leiden Univ, Med Ctr, Dept Med Stat & Bioinformat, NL-2300 RC Leiden, Netherlands
关键词
genetic linkage; siblings; thromboembolism; thrombophilia; thrombosis; PROTEIN-C DEFICIENCY; DEEP-VEIN THROMBOSIS; ABO BLOOD-GROUP; FACTOR-V-LEIDEN; RISK-FACTORS; THROMBOPHILIA; VARIANTS; DISEASE; ASSOCIATION; DISORDER;
D O I
10.1111/jth.12313
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Venous thromboembolism (VTE) is a multicausal disorder involving environmental and genetic risk factors. In many thrombophilic families the clustering of thrombotic events cannot be explained by known genetic risk factors, indicating that some remain to be discovered. Objectives: We aimed to identify novel thrombosis susceptibility alleles in a large panel of small thrombophilic families: the Genetics In Familial Thrombosis (GIFT) study. Patients/Methods: In the GIFT study, 201 families were recruited consisting of 438 siblings with an objectively confirmed VTE at a young age. Multipoint linkage analysis (402 SSR markers) and fine mapping were performed, followed by genotyping of tagging SNPs in positional candidate genes. Results: Established genetic risk factors such as factor V Leiden, ABO blood group non-O, prothrombin 20210A, fibrinogen gamma 10034T and deficiencies of antithrombin, protein C and protein S were more frequent in GIFT patients than in unselected VTE patients. Linkage supported the presence of novel thrombosis susceptibility loci on 7p21.3-22.2 (LOD score = 3.23) and Xq24-27.3 (LOD score = 1.95). Simulation analysis showed that the chr7 signal was genome-wide statistically significant (P = 0.022). Tagging SNPs (n = 157) in eight positional candidate genes (LOD drop 1.5 regions) were genotyped in GIFT patients and 332 healthy controls. Five chr7 SNPs associated with VTE. SNP THSD7A rs2074597 was responsible for part of the chr7 signal. Conclusions: The GIFT panel is rich in established genetic risk factors for VTE, but genetic factors remain unidentified in many families. Genome-wide linkage failed to identify the previously established genetic risk factors for VTE, but identified a novel VTE susceptibility locus on chr7.
引用
收藏
页码:1474 / 1484
页数:11
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