Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF
Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF
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DOI：
10.1182/blood-2015-02-624551
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发表时间：
2015-09-10
期刊：
影响因子：
20.3
通讯作者：
Smith, Nicholas L.
中科院分区：
文献类型：
--
作者：
Huffman, Jennifer E.;de Vries, Paul S.;Smith, Nicholas L.
纤维蛋白原、凝血因子VII（FVII）和因子VIII（FVIII）及其载体血管性血友病因子（vWF）在止血过程中起关键作用。先前确定的常见变异仅能解释该性状遗传力的一小部分，而其他变异可能由与效应更大的罕见变异的关联来解释。本研究的目的是通过对来自4个族裔的多达76000名参与者的外显子芯片数据进行荟萃分析，确定影响这4种止血因子血浆浓度的低频（次要等位基因频率[MAF]≥0.01且<0.05）和罕见（MAF<0.01）变异。我们在纤维蛋白原、FVII、FVIII和vWF性状中确定了12种低频（n = 2）和罕见（n = 10）变异的新型关联，这些关联独立于先前确定的关联。在先前报道的基因中发现了新的基因座，其效应大小远大于且独立于先前确定的常见变异。此外，在KCNT1、HID1和KATNB1处的关联确定了与止血相关的新的候选基因，以便进行后续的复制和功能基因组分析。新确定的低频和罕见变异关联对性状方差的解释量适中，因此不太可能增加预测的性状遗传力，但为理解止血途径中的个体差异提供了新信息。
Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] >= 0.01 and < 0.05) and rare (MAF < 0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76 000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n=2) andrare (n=10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.