Genetic determinants of normal variation in coagulation factor (F) IX levels: genome-wide scan and examination of the FIX structural gene
Genetic determinants of normal variation in coagulation factor (F) IX levels: genome-wide scan and examination of the FIX structural gene
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DOI：
10.1111/j.1538-7836.2006.02024.x
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发表时间：
2006-07-01
影响因子：
10.4
通讯作者：
Howard, T. E.
中科院分区：
文献类型：
--
作者：
Khachidze, M.;Buil, A.;Howard, T. E.
背景资料：血浆FIX活性（FIX：C）水平正常高值和升高与静脉血栓形成和可能的动脉血栓形成风险增加相关。目的：由于FIX：C的广泛正常范围涉及大量未知的遗传成分，因此我们试图确定这一具有医学重要性的止血性状的数量性状基因座（QTL）。研究方法：我们在特发性血栓形成倾向项目（GAIT）的遗传分析中对每个不同FIX基因（179）的已知功能区域进行了全基因组筛选和基于重测序的变异扫描，该项目收集了来自21个家系的398名西班牙白人。结果：尽管对超过540个均匀分布的微卫星进行了基因分型，但我们没有发现连锁的证据（LOD评分< 1.5）。我们确定了27个候选的F9多态性，包括3个顺式元件，负责增加FIX：C，发生与老化，但没有发现显着的基因型特异性差异，平均FIX：C水平（P值>= 0.11），尽管评估每一个多态性GAIT边缘多协变量测量基因型关联分析。结论：个体间FIX：C变异性的遗传成分可能涉及一组具有适度影响的QTL，这些QTL可能存在于F9以外的基因中。然而，由于这27个多态性的等位基因表现出较低的整体程度的连锁不平衡，我们目前正在定义其单倍型，以询问几个高度保守的非外显子序列和其他F9片段没有在这里检查。
Background: High-normal and elevated plasma FIX activity (FIX:C) levels are associated with increased risk for venous- and possibly arterial-thrombosis. Objective: Because the broad normal range for FIX:C involves a substantial unknown genetic component, we sought to identify quantitative-trait loci (QTLs) for this medically important hemostasis trait. Methods: We performed a genome-wide screen and a resequencing-based variation scan of the known functional regions of every distinct FIX gene (179) in the genetic analysis of idiopathic thrombophilia project (GAIT), a collection of 398 Spanish-Caucasians from 21 pedigrees. Results: We found no evidence for linkage (LOD scores < 1.5) despite genotyping more than 540 uniformly-spaced microsatellites. We identified 27 candidate F9 polymorphisms, including three in cis-elements responsible for the increase in FIX:C that occurs with aging, but found no significant genotype-specific differences in mean FIX:C levels (P-values >= 0.11) despite evaluating every polymorphism in GAIT by marginal multicovariate measured-genotype association analysis. Conclusions: The heritable component of interindividual FIX:C variability likely involves a collection of QTLs with modest effects that may reside in genes other than F9. Nevertheless, because the alleles of these 27 polymorphisms exhibited a low overall degree of linkage disequilibrium, we are currently defining their haplotypes to interrogate several highly-conserved non-exonic sequences and other F9 segments not examined here.