C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies
C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies
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DOI：
10.1182/blood-2010-01-263038
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发表时间：
2010-06-10
期刊：
影响因子：
20.3
通讯作者：
Morange, Pierre-Emmanuel
中科院分区：
文献类型：
--
作者：
Buil, Alfonso;Tregouet, David-Alexandre;Morange, Pierre-Emmanuel
c4b结合蛋白（C4BP）通过与凝血/纤溶级联的关键元素蛋白S （PS）结合，被认为参与了静脉血栓形成（VT）的易感性。为了确定可能影响血浆中现有的3 C4BP亚型α (7) β(1)、α (6) β(1)和α (7) β(0)水平的遗传因素，我们在352人组成的特发性血栓性疾病遗传分析（步态）研究中，通过分析283 437个单核苷酸多态性（snp）进行了全基因组关联研究。在C4BPB/C4BPA位点上发现了3个snp与α (7) β(0)水平在全基因组范围内显著相关。在由1490人组成的古登堡心脏研究中，其中一个snp被进一步发现可以解释大约11%的C4BPA mRNA表达变异性，而对C4BPB mRNA表达没有影响。在两项独立的病例对照研究（马赛血栓协会研究[MARTHA]和血栓栓塞性静脉病变因子研究[FARIVE]）中，发现与α (7) β(0)血浆水平升高和C4BPA表达升高相关的等位基因与VT风险增加相关（优势比[OR] = 1.24[1.03-1.53]），该研究收集了1706例病例和1379例对照。该SNP与游离PS或总PS无关。综上所述，我们观察到强有力的证据表明，C4BPB/C4BPA位点是VT的一个新的易感位点，其与PS无关的机制仍有待阐明。(血。2010;115 (23):4644 - 4650)
Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, alpha(7)beta(1), alpha(6)beta(1), and alpha(7)beta(0), we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with alpha(7)beta(0) levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased alpha(7)beta(0) plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de recidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated. (Blood. 2010;115(23):4644-4650)