Ma Qianyi, Jacobi Paula M, Emmer Brian T, Kretz Colin A, Ozel Ayse Bilge, McGee Beth, Kimchi-Sarfaty Chava, Ginsburg David, Li Jun Z, Desch Karl C
Department of Human Genetics.
Department of Pediatrics and Communicable Disease.
Blood Adv. 2017 Jun 19;1(15):1037-1046. doi: 10.1182/bloodadvances.2017005629. eCollection 2017 Jun 27.
The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) in circulating blood, limiting the size of VWF multimers and regulating VWF activity. Abnormal regulation of VWF contributes to bleeding and to thrombotic disorders. ADAMTS13 levels in plasma are highly variable among healthy individuals, although the heritability and the genetic determinants of this variation are unclear. We performed genome-wide association studies of plasma ADAMTS13 concentrations in 3244 individuals from 2 independent cohorts of healthy individuals. The heritability of ADAMTS13 levels was between 59.1% (all individuals) and 83.5% (siblings only), whereas tobacco smoking was associated with a decrease in plasma ADAMTS13 levels. Meta-analysis identified common variants near the locus on chromosome 9q34.2 that were significantly associated with ADAMTS13 levels and collectively explained 20.0% of the variance. The top single nucleotide polymorphism (SNP), rs28673647, resides in an intron of (β, 6.7%; = 1.3E-52). Conditional analysis revealed 3 additional independent signals represented by rs3739893 (β, -22.3%; = 1.2E-30) and rs3124762 (β, 3.5%; = 8.9E-9) close to and rs4075970 (β, 2.4%; = 6.8E-9) on 21q22.3. Linkage analysis also identified the region around (9q34.2) as the top signal (LOD 3.5), consistent with our SNP association analyses. Two nonsynonymous variants in the top 2 independent linkage disequilibrium blocks (Q448E and A732V) were identified and characterized in vitro. This study uncovered specific common genetic polymorphisms that are key genetic determinants of the variation in plasma ADAMTS13 levels in healthy individuals.
金属蛋白酶ADAMTS13可切割循环血液中的血管性血友病因子（VWF），限制VWF多聚体的大小并调节VWF活性。VWF的异常调节会导致出血和血栓形成性疾病。血浆中ADAMTS13水平在健康个体中高度可变，尽管这种变异的遗传力和遗传决定因素尚不清楚。我们对来自2个独立健康个体队列的3244名个体的血浆ADAMTS13浓度进行了全基因组关联研究。ADAMTS13水平的遗传力在59.1%（所有个体）至83.5%（仅兄弟姐妹）之间，而吸烟与血浆ADAMTS13水平降低有关。荟萃分析确定了9号染色体q34.2位点附近的常见变异，这些变异与ADAMTS13水平显著相关，共同解释了20.0%的变异。最显著的单核苷酸多态性（SNP）rs28673647位于（β，6.7%；=1.3E - 52）的一个内含子中。条件分析揭示了另外3个独立信号，分别由靠近的rs3739893（β，-22.3%；=1.2E - 30）和rs3124762（β，3.5%；=8.9E - 9）以及21号染色体q22.3上的rs4075970（β，2.4%；=6.8E - 9）代表。连锁分析也确定了（9q34.2）周围区域为最强信号（LOD 3.5），与我们的SNP关联分析一致。在体外鉴定并表征了前2个独立连锁不平衡块中的2个非同义变体（Q448E和A732V）。这项研究发现了特定的常见基因多态性，这些多态性是健康个体血浆ADAMTS13水平变异的关键遗传决定因素。
