Khanna Ritesh, Nandy Debparna, Senapati Sabyasachi
Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India.
Front Genet. 2019 May 16;10:413. doi: 10.3389/fgene.2019.00413. eCollection 2019.
Vitamin-D binding protein (DBP) also known as GC protein, is a major determinant for vitamin- D metabolism and transport. GC1F, GC1S, and GC2 are the three allelic variants (denoted as rs4588 and rs7041) of GC, and known to be associated with chronic obstructive pulmonary disease (COPD). However, contradictory reports and population specific risk attributed by these alleles warranted detailed genetic epidemiology study to establish the association between GC variants and COPD. In this study we performed a meta-analysis and investigated the genetic architecture of GC locus to establish the association and uncover the plausible reason for allelic heterogeneity. Published cross-sectional case control studies were screened and meta-analysis was performed between GC variants and COPD outcome. RevMan-v5.3 software was used to perform random and/or fixed models to calculate pooled odds ratio (Meta-OR). Linkage disequilibrium (LD) and haplotypes at GC locus were evaluated using 1000 Genomes genotype data. functional implications of rs4588 and rs7041 was tested using publicly available tools. GC1F allele and GC1F/1F genotype were found to confer COPD risk in overall meta-analysis. GC1S/1S was found to confer risk only among Europeans. investigation of rs4588 and rs7041 identified strong eQTL effects and potential role in regulation of GC expression. Large differences in allele frequencies, linkage disequilibrium (LD) and haplotypes were identified at GC locus across different populations (Japanese, African, Europeans, and Indians), which may explain the variable association of different GC alleles in different populations. GC1F and GC1F/1F impose significant genetic risk for COPD, among Asians. Considerable differences in allele frequencies and LD structure in GC locus may impose population specific risk.
维生素D结合蛋白（DBP）也被称为GC蛋白，是维生素D代谢和转运的主要决定因素。GC1F、GC1S和GC2是GC的三种等位基因变体（表示为rs4588和rs7041），已知与慢性阻塞性肺疾病（COPD）相关。然而，这些等位基因导致的相互矛盾的报道以及特定人群的风险，使得有必要进行详细的遗传流行病学研究，以确定GC变体与COPD之间的关联。在本研究中，我们进行了一项荟萃分析，并研究了GC基因座的遗传结构，以确定这种关联，并揭示等位基因异质性的可能原因。我们筛选了已发表的横断面病例对照研究，并对GC变体与COPD结局进行了荟萃分析。使用RevMan-v5.3软件进行随机和/或固定模型分析，以计算合并比值比（Meta-OR）。使用千人基因组基因型数据评估GC基因座的连锁不平衡（LD）和单倍型。使用公开可用的工具测试rs4588和rs7041的功能影响。在总体荟萃分析中发现，GC1F等位基因和GC1F/1F基因型会增加患COPD的风险。仅在欧洲人中发现GC1S/1S会增加风险。对rs4588和rs7041的研究确定了其强大的表达数量性状基因座（eQTL）效应以及在调节GC表达中的潜在作用。在不同人群（日本人、非洲人、欧洲人和印度人）的GC基因座上，发现等位基因频率、连锁不平衡（LD）和单倍型存在很大差异，这可能解释了不同GC等位基因在不同人群中的可变关联。在亚洲人中，GC1F和GC1F/1F会给COPD带来显著的遗传风险。GC基因座中等位基因频率和LD结构的显著差异可能导致特定人群的风险。
