凝血因子 XIII - A 亚基基因中六个单核苷酸多态性的连锁与关联表明 V34L 是主要功能位点。

Joint linkage and association of six single-nucleotide polymorphisms in the factor XIII-A subunit gene point to V34L as the main functional locus.

作者信息

de Lange Marlies, Andrew Toby, Snieder Harold, Ge Dongliang, Futers T Simon, Standeven Kristina, Spector Tim D, Grant Peter J, Ariëns Robert A S

机构信息

Twin Research & Genetic Epidemiology Unit, St Thomas' Hospital, London, UK.

出版信息

Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1914-9. doi: 10.1161/01.ATV.0000231538.60223.92. Epub 2006 Jun 8.

DOI:10.1161/01.ATV.0000231538.60223.92

PMID:16763156

Abstract

OBJECTIVE

Activated factor XIII (FXIII) crosslinks fibrin to enhance the mechanical strength of a blood clot and increase its resistance to fibrinolysis. The prevalence of a common variant in the FXIII-A gene (V34L) has been reported to be lower in patients with myocardial infarction and ischemic stroke than in controls, suggesting a protective role for this polymorphism in vascular diseases. The current study investigated 6 single-nucleotide polymorphisms (SNPs) within the FXIII A-subunit gene to locate functional polymorphism(s) responsible for variation in FXIII activation.

METHODS AND RESULTS

A total of 201 dizygotic twin pairs were genotyped for 1 promoter and all common nonsynonymous coding polymorphisms in the FXIII A-subunit gene: -246G>A, V34L, Y204F, P564L, V650I, and E651Q. Tests of linkage, association, and combined linkage and association were performed using QTDT software. Significant linkage to the V34L polymorphism (P=5 x 10(-12)) as well as association (P=3 x 10(-49)) was observed. Adjusting for association while performing linkage made the linkage signal disappear for the V34L polymorphism (from chi2=47.55, P=5x10(-12) to chi2=1.30, P=0.25). Only haplotypes containing the 34L allele showed association with FXIII activation.

CONCLUSIONS

Testing multiple SNPs in the FXIII A-subunit gene indicates that V34L is the main functional polymorphism influencing FXIII activation.

摘要

目的

活化的凝血因子 XIII（FXIII）可交联纤维蛋白，增强血凝块的机械强度并提高其抗纤维蛋白溶解能力。据报道，心肌梗死和缺血性中风患者中 FXIII - A 基因常见变异（V34L）的发生率低于对照组，这表明该多态性在血管疾病中具有保护作用。本研究调查了 FXIII A 亚基基因内的 6 个单核苷酸多态性（SNP），以定位导致 FXIII 活化变异的功能性多态性。

方法与结果

对 201 对异卵双胞胎进行基因分型，检测 FXIII A 亚基基因的 1 个启动子及所有常见的非同义编码多态性：-246G>A、V34L、Y204F、P564L、V650I 和 E651Q。使用 QTDT 软件进行连锁、关联以及连锁与关联相结合的检验。观察到与 V34L 多态性存在显著连锁（P = 5×10⁻¹²）以及关联（P = 3×10⁻⁴⁹）。在进行连锁分析时调整关联因素后，V34L 多态性的连锁信号消失（从 chi² = 47.55，P = 5×10⁻¹² 变为 chi² = 1.30，P = 0.25）。只有包含 34L 等位基因的单倍型与 FXIII 活化相关。