Shendre Aditi, Wiener Howard W, Irvin Marguerite R, Aouizerat Bradley E, Overton Edgar T, Lazar Jason, Liu Chenglong, Hodis Howard N, Limdi Nita A, Weber Kathleen M, Gange Stephen J, Zhi Degui, Floris-Moore Michelle A, Ofotokun Ighovwerha, Qi Qibin, Hanna David B, Kaplan Robert C, Shrestha Sadeep
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Bluestone Center for Clinical Research, New York University, New York, New York, United States of America.
PLoS One. 2017 Dec 4;12(12):e0188725. doi: 10.1371/journal.pone.0188725. eCollection 2017.
Cardiovascular disease (CVD) is a major comorbidity among HIV-infected individuals. Common carotid artery intima-media thickness (cCIMT) is a valid and reliable subclinical measure of atherosclerosis and is known to predict CVD. We performed genome-wide association (GWA) and admixture analysis among 682 HIV-positive and 288 HIV-negative Black, non-Hispanic women from the Women's Interagency HIV study (WIHS) cohort using a combined and stratified analysis approach. We found some suggestive associations but none of the SNPs reached genome-wide statistical significance in our GWAS analysis. The top GWAS SNPs were rs2280828 in the region intergenic to mediator complex subunit 30 and exostosin glycosyltransferase 1 (MED30 | EXT1) among all women, rs2907092 in the catenin delta 2 (CTNND2) gene among HIV-positive women, and rs7529733 in the region intergenic to family with sequence similarity 5, member C and regulator of G-protein signaling 18 (FAM5C | RGS18) genes among HIV-negative women. The most significant local European ancestry associations were in the region intergenic to the zinc finger and SCAN domain containing 5D gene and NADH: ubiquinone oxidoreductase complex assembly factor 1 (ZSCAN5D | NDUF1) pseudogene on chromosome 19 among all women, in the region intergenic to vomeronasal 1 receptor 6 pseudogene and zinc finger protein 845 (VN1R6P | ZNF845) gene on chromosome 19 among HIV-positive women, and in the region intergenic to the SEC23-interacting protein and phosphatidic acid phosphatase type 2 domain containing 1A (SEC23IP | PPAPDC1A) genes located on chromosome 10 among HIV-negative women. A number of previously identified SNP associations with cCIMT were also observed and included rs2572204 in the ryanodine receptor 3 (RYR3) and an admixture region in the secretion-regulating guanine nucleotide exchange factor (SERGEF) gene. We report several SNPs and gene regions in the GWAS and admixture analysis, some of which are common across HIV-positive and HIV-negative women as demonstrated using meta-analysis, and also across the two analytic approaches (i.e., GWA and admixture). These findings suggest that local European ancestry plays an important role in genetic associations of cCIMT among black women from WIHS along with other environmental factors that are related to CVD and may also be triggered by HIV. These findings warrant confirmation in independent samples.
心血管疾病（CVD）是HIV感染者中的一种主要合并症。颈总动脉内膜中层厚度（cCIMT）是动脉粥样硬化一种有效且可靠的亚临床指标，并且已知可预测心血管疾病。我们使用联合分层分析方法，对来自女性机构间HIV研究（WIHS）队列的682名HIV阳性和288名HIV阴性的黑人非西班牙裔女性进行了全基因组关联（GWA）和混合分析。我们发现了一些提示性关联，但在我们的GWAS分析中，没有一个单核苷酸多态性（SNP）达到全基因组统计学显著性。在所有女性中，GWAS排名靠前的SNP是位于中介体复合物亚基30和外切糖苷酶1（MED30 | EXT1）基因间区域的rs2280828；在HIV阳性女性中，是连环蛋白δ2（CTNND2）基因中的rs2907092；在HIV阴性女性中，是位于序列相似性家族5成员C和G蛋白信号调节剂18（FAM5C | RGS18）基因间区域的rs7529733。最显著的本地欧洲血统关联在所有女性中位于19号染色体上含锌指和SCAN结构域的5D基因与NADH：泛醌氧化还原酶复合物组装因子1（ZSCAN5D | NDUF1）假基因的基因间区域；在HIV阳性女性中，位于19号染色体上犁鼻器1受体6假基因和锌指蛋白845（VN1R6P | ZNF845）基因的基因间区域；在HIV阴性女性中，位于10号染色体上SEC23相互作用蛋白和含2型磷脂酸磷酸酶结构域1A（SEC23IP | PPAPDC1A）基因的基因间区域。还观察到一些先前确定的与cCIMT相关的SNP关联，包括兰尼碱受体3（RYR3）中的rs2572204和分泌调节鸟嘌呤核苷酸交换因子（SERGEF）基因中的一个混合区域。我们在GWAS和混合分析中报告了几个SNP和基因区域，其中一些在HIV阳性和HIV阴性女性中是共有的，如通过荟萃分析所示，并且在两种分析方法（即GWA和混合分析）中也是共有的。这些发现表明，本地欧洲血统在WIHS黑人女性cCIMT的遗传关联中起重要作用，同时还有其他与心血管疾病相关的环境因素，并且可能也由HIV引发。这些发现需要在独立样本中得到证实。
