A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q.
A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q.
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DOI：
10.1111/j.1538-7836.2012.04810.x
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
De Andrade M
中科院分区：
文献类型：
--
作者：
Heit JA;Armasu SM;Asmann YW;Cunningham JM;Matsumoto ME;Petterson TM;De Andrade M
确定静脉血栓栓塞症（VTE）疾病易感基因。我们使用基因型数据进行了计算机全基因组关联（GWAS）分析，这些基因型数据来自客观诊断为VTE的成人（n=1503）和年龄和性别频率匹配的对照组（n=1459;发现人群）的约250万个单核苷酸多态性（SNP）。超过全基因组显著性的SNP在单独的人群中复制（VTE病例，n=1407;对照，n=1418）。与VTE相关的基因被重新测序。7个SNP超过全基因组显著性（P < 5 × 10-8）; 4个在染色体1q24.2上（F5 rs6025 [凝血因子V Leiden]、BLZF 1 rs7538157、NME 7 rs 16861990和SLC 19 A2 rs 2038024）和染色体9q34.2上的三个（ABO rs 2519093 [ABO内含子1]，rs 495828，rs 8176719 [ABO血型O等位基因]）。复制研究证实F5、NME 7和ABO与VTE显著相关。然而，F5是1q24.2上的主要信号，因为在调整F5 rs6025后，只有ABO SNP仍与VTE显著相关。该1q24.2区域显示为作为单倍型块遗传。ABO基因重测序鉴定出15个新的单核苷酸变异（SNV），位于ABO内含子6和ABO 3' UTR，与VTE密切相关（P < 10-4），属于3个不同的连锁不平衡（LD）区块;没有一个与ABO rs 8176719或rs 2519093连锁不平衡。我们的样本量提供了80%的把握度来检测次要等位基因频率分别为0.05和0.5的比值比=2.0和1.51（α=1 × 10-8; 1% VTE患病率）。除了F5 rs6025、ABO rs 8176719和rs 2519093以及F2 rs 1799963之外，白人中不太可能存在其他常见和高VTE风险的SNP。
To identify venous thromboembolism (VTE) disease-susceptibility genes. We performed in silico genome wide association (GWAS) analyses using genotype data imputed to ~2.5 million single nucleotide polymorphisms (SNPs) from adults with objectively-diagnosed VTE (n=1503), and controls frequency-matched on age and sex (n=1459; discovery population). SNPs exceeding genome-wide significance were replicated in a separate population (VTE cases, n=1407; controls, n=1418). Genes associated with VTE were resequenced. Seven SNPs exceeded genome-wide significance (P < 5 × 10-8); four on chromosome 1q24.2 (F5 rs6025 [Factor V Leiden], BLZF1 rs7538157, NME7 rs16861990 and SLC19A2 rs2038024) and three on chromosome 9q34.2 (ABO rs2519093 [ABO intron 1], rs495828, rs8176719 [ABO blood type O allele]). The replication study confirmed a significant association of F5, NME7, and ABO with VTE. However, F5 was the main signal on 1q24.2 as only ABO SNPs remained significantly associated with VTE after adjusting for F5 rs6025. This 1q24.2 region was shown to be inherited as a haplotype block. ABO resequencing identified 15 novel single nucleotide variations (SNV) in ABO intron 6 and the ABO 3’ UTR that were strongly associated with VTE (P < 10-4) and belonged to three distinct linkage disequilibrium (LD) blocks; none were in LD with ABO rs8176719 or rs2519093. Our sample size provided 80% power to detect odds ratios=2.0 and 1.51 for minor allele frequencies=0.05 and 0.5, respectively (α=1 × 10-8; 1% VTE prevalence). Aside from F5 rs6025, ABO rs8176719 and rs2519093, and F2 rs1799963, additional common and high VTE-risk SNPs among whites are unlikely.
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影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
10.4
作者：
Heit, JA;Petterson, TM;Melton, LJ
通讯作者：
Melton, LJ
DOI：
10.1073/pnas.90.3.1004
发表时间：
1993-02-01
影响因子：
11.1
作者：
DAHLBACK, B;CARLSSON, M;SVENSSON, PJ
通讯作者：
SVENSSON, PJ
影响因子：
--
作者：
Heit, JA;Silverstein, MD;Melton, LJ
通讯作者：
Melton, LJ
影响因子：
4.8
作者：
KALAFATIS, M;BERTINA, RM;MANN, KG
通讯作者：
MANN, KG