Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.
Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.
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DOI：
10.1161/circulationaha.109.869156
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发表时间：
2010-03-30
期刊：
影响因子：
37.8
通讯作者：
O'Donnell CJ
中科院分区：
文献类型：
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作者：
Smith NL;Chen MH;Dehghan A;Strachan DP;Basu S;Soranzo N;Hayward C;Rudan I;Sabater-Lleal M;Bis JC;de Maat MP;Rumley A;Kong X;Yang Q;Williams FM;Vitart V;Campbell H;Mälarstig A;Wiggins KL;Van Duijn CM;McArdle WL;Pankow JS;Johnson AD;Silveira A;McKnight B;Uitterlinden AG;Wellcome Trust Case Control Consortium;;Aleksic N;Meigs JB;Peters A;Koenig W;Cushman M;Kathiresan S;Rotter JI;Bovill EG;Hofman A;Boerwinkle E;Tofler GH;Peden JF;Psaty BM;Leebeek F;Folsom AR;Larson MG;Spector TD;Wright AF;Wilson JF;Hamsten A;Lumley T;Witteman JC;Tang W;O'Donnell CJ
凝血因子VII（FVII）、VIII（FVIII）和血管性血友病因子（vWF）的血浆水平影响出血和血栓形成的风险。我们进行了全基因组关联研究以确定与血浆水平相关的新位点。
研究环境包括5项基于社区的发现性研究，涵盖23608名欧洲血统的参与者：ARIC、CHS、B58C、FHS和RS。所有研究都进行了全基因组单核苷酸多态性（SNP）扫描，并且至少测量了1种表型：FVII活性/抗原、FVIII活性和vWF抗原。每项研究都使用其基因型数据来推断HapMap SNPs，并使用加性遗传模型独立地对止血指标进行关联分析。通过荟萃分析整合研究结果。在7604名未参与发现队列的参与者中进行了重复验证。对于FVII，305个SNP超过了全基因组显著性阈值5.0×10⁻⁸，并在5条染色体上包含5个位点：2p23（最小P值为6.2×10⁻²⁴）、4q25（3.6×10⁻¹²）、11q12（2.0×10⁻¹⁰）、13q34（9.0×10⁻²⁵⁹）和20q11.2（5.7×10⁻³⁷）。这些位点位于基因内部或附近，包括4个新的候选基因和F7（13q34）。对于vWF，400个SNP超过了阈值，并在6条染色体上标记了8个位点：6q24（1.2×10⁻²²）、8p21（1.3×10⁻¹⁶）、9q34（<5.0×10⁻³²⁴）、12p13（1.7×10⁻³²）、12q23（7.3×10⁻¹⁰）、12q24.3（3.8×10⁻¹¹）、14q32（2.3×10⁻¹⁰）和19p13.2（1.3×10⁻⁹）。所有位点都在基因内部，包括6个新的候选基因，以及ABO（9q34）和VWF（12p13）。对于FVIII，确定了5个位点，且与vWF的研究结果有重叠。10个新发现中有9个得到了重复验证。
在先前已知的生物学途径之外发现了新的遗传关联，这可能指向止血障碍的新型预防和治疗靶点。
Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. Setting includes 5 community-based studies for discovery comprising 23,608 European-ancestry participants: ARIC, CHS, B58C, FHS, and RS. All had genome-wide single nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7,604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0×10−8 and comprised 5 loci on 5 chromosomes: 2p23 (smallest p-value 6.2×10−24), 4q25 (3.6×10−12), 11q12 (2.0×10−10), 13q34 (9.0×10−259), and 20q11.2 (5.7×10−37). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2×10−22), 8p21 (1.3×10−16), 9q34 (<5.0×10−324), 12p13 (1.7×10−32), 12q23 (7.3×10−10), 12q24.3 (3.8×10−11), 14q32 (2.3×10−10) and 19p13.2 (1.3×10−9). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings replicated. New genetic associations were discovered outside previously known biologic pathways and may point to novel prevention and treatment targets of hemostasis disorders.