A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels
A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels
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DOI：
10.1182/blood-2006-06-026104
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发表时间：
2007-05-01
期刊：
影响因子：
20.3
通讯作者：
Howard, Tom E.
中科院分区：
文献类型：
--
作者：
Viel, Kevin R.;Machiah, Deepa K.;Howard, Tom E.
血浆凝血因子凝血活性(FVIII：C)水平是一种高度可遗传的数量性状，与血栓形成风险密切相关。只有1个基因(ABO血型基因座)内的多态已被明确证明有助于观察到这一特征的广泛群体变异性。由于之前只检测了不到2.5%的FVIII结构基因(F8)，我们对代表7个种族的137名无关非血友病个体的222个潜在不同等位基因的所有已知功能区域进行了重新测序。在已鉴定的47个变异中，有18个是以前未知的，其中包括17个单核苷酸多态(SNPs)。由于F8之间的连锁不平衡程度总体上很弱，我们使用测量-基因关联分析来评估来自21个家系的398名受试者的FVIII：C水平的影响，这被称为特发性血栓形成遗传分析项目(GATIT)。我们的结果表明，编码B区替换D1241E的非同义SNP 92714C>；G与FVIII：C水平显著相关。在考虑了包括年龄和ABO基因型在内的重要协变量后，这种关联持续存在，每个C等位基因都使FVIII：C水平增加了14.3IU dL(-1)(P=0.016)。然而，由于56010G和GT；A的等位基因与步态中的92714C和GT；G密切相关，因此需要进一步的研究来确定D1241E本身是否是一个功能变异。(C)2007年由美国血液病学会公布。
Plasma factor VIII coagulant activity (FVIII:C) level is a highly heritable quantitative trait that is strongly correlated with thrombosis risk. Polymorphisms within only 1 gene, the ABO blood-group locus, have been unequivocally demonstrated to contribute to the broad population variability observed for this trait. Because less than 2.5% of the structural FVIII gene (F8) has been examined previously, we resequenced all known functional regions in 222 potentially distinct alleles from 137 unrelated nonhemophilic individuals representing 7 racial groups. Eighteen of the 47 variants identified, including 17 single-nucleotide polymorphisms (SNPs), were previously unknown. As the degree of linkage disequilibrium across F8 was weak overall, we used measured-genotype association analysis to evaluate the influence of each polymorphism on the FVIII:C levels in 398 subjects from 21 pedigrees known as the Genetic Analysis of Idiopathic Thrombophilia project (GAIT). Our results suggested that 92714C>G, a nonsynonymous SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C level. After accounting for important co-variates, including age and ABO genotype, the association persisted with each C-allele additively increasing the FVIII:C level by 14.3 IU dL(-1) (P = .016). Nevertheless, because the alleles of 56010G>A, a SNP within the 3' splice junction of intron 7, are strongly associated with 92714C>G in GAIT, additional studies are required to determine whether D1241E is itself a functional variant. (C) 2007 by The American Society of Hematology.