Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.
Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.
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DOI：
10.1080/09537104.2017.1384538
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发表时间：
2019
期刊：
影响因子：
3.3
通讯作者：
Faraday N
中科院分区：
文献类型：
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作者：
Chen MH;Yanek LR;Backman JD;Eicher JD;Huffman JE;Ben-Shlomo Y;Beswick AD;Yerges-Armstrong LM;Shuldiner AR;O'Connell JR;Mathias RA;Becker DM;Becker LC;Lewis JP;Johnson AD;Faraday N
以前的全基因组关联研究（GWAS）已经确定了几个与血小板功能表型相关的变异;然而，由所确定的变异解释的变异比例大多很小。罕见的编码变体，特别是那些对蛋白质结构/功能具有高潜在影响的变体，可能对表型有实质性影响，但难以通过GWAS检测。本研究的主要目的是使用来自Illumina HumanExome Bead Chip的基因型数据鉴定与血小板功能相关的低频率或罕见变异。三个基于家族的欧洲血统队列（包括约4，000名受试者）组成了发现队列，两个独立队列（一个欧洲血统和一个非裔美国人血统）用于复制。在所有发现队列中对腺苷二磷酸（ADP）、肾上腺素和胶原蛋白进行富血小板血浆光学聚集测定。使用基于基因的方法和单核苷酸变异关联方法进行荟萃分析。基于基因的荟萃分析发现ANKRD 26中罕见的遗传变异与ADP诱导的血小板聚集之间存在显著相关性（P=7.13 × 10−7）。其中一个ANKRD 26 SNV-rs 191015656，编码一个苏氨酸到异亮氨酸的取代，预计会改变蛋白质的结构/功能，在欧洲人中复制。在所有队列的杂合子中观察到聚集增加约20-50%。在荟萃分析中，ABCG 1和HCP 5中的新遗传信号也与血小板聚集至ADP相关，尽管只有HCP 5的结果可以重复。HCP 5中的SNV与CD 41+巨核细胞中的表观遗传特征交叉，表明HCP 5在血小板生物学中的新功能作用。这是第一项使用基于基因的SNV阵列基因型关联方法来识别与血小板功能相关的罕见变异的研究。分子机制和病理生理学的相关性，为确定的遗传协会需要进一步研究。
Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort, and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P=7.13 × 10−7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20–50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.