Jia Peilin, Zhao Zhongming, Hulgan Todd, Bush William S, Samuels David C, Bloss Cinnamon S, Heaton Robert K, Ellis Ronald J, Schork Nicholas, Marra Christina M, Collier Ann C, Clifford David B, Gelman Benjamin B, Sacktor Ned, Morgello Susan, Simpson David M, McCutchan J Allen, Barnholtz-Sloan Jill S, Franklin Donald R, Rosario Debralee, Letendre Scott L, Grant Igor, Kallianpur Asha R
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, Texas.
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee.
Am J Med Genet B Neuropsychiatr Genet. 2017 Jun;174(4):413-426. doi: 10.1002/ajmg.b.32530. Epub 2017 Apr 26.
HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS ≥ 0.5 and 684 controls with GDS < 0.5, and GDS as a continuous variable) and Frascati HAND definitions that incorporate assessment of functional impairment by self-report and performance-based criteria. Genotype data were obtained using the Affymetrix Human SNP Array 6.0 platform. Multivariable logistic or linear regression-based association tests were performed for GDS-defined NCI and HAND. GWAS results did not reveal SNPs meeting the genome-wide significance threshold (5.0 × 10 ) for GDS-defined NCI or HAND. For binary GDS, the most significant SNPs were rs6542826 (P = 8.1 × 10 ) and rs11681615 (1.2 × 10 ), both located on chromosome 2 in SH3RF3. The most significant SNP for continuous GDS was rs11157436 (P = 1.3 × 10 ) on chromosome 14 in the T-cell-receptor alpha locus; three other SNPs in this gene were also associated with binary GDS (P ≤ 2.9 × 10 ). This GWAS, conducted among ART-era participants from a single cohort with robust neurological phenotyping, suggests roles for several biologically plausible loci in HAND that deserve further exploration. © 2017 Wiley Periodicals, Inc.
尽管采用了联合抗逆转录病毒疗法（ART），但人类免疫缺陷病毒相关神经认知障碍（HAND）仍常使HIV感染复杂化，且可能受宿主基因组学影响。我们对1050名中枢神经系统HIV抗逆转录病毒治疗效果研究（CHARTER）的参与者进行了HAND的全基因组关联研究（GWAS）。所有参与者都接受了标准化、全面的神经认知和神经医学评估，以根据全球缺陷评分（GDS）确定他们是否存在认知障碍，患有可能混淆HAND诊断的合并症的个体被排除。神经认知结果包括GDS定义的神经认知障碍（NCI；二元GDS，366例GDS≥0.5，684例对照GDS<0.5，以及GDS作为连续变量）和弗拉斯卡蒂HAND定义，该定义纳入了通过自我报告和基于表现的标准对功能障碍的评估。使用Affymetrix人类SNP Array 6.0平台获取基因型数据。对GDS定义的NCI和HAND进行了基于多变量逻辑或线性回归的关联测试。GWAS结果未揭示达到GDS定义的NCI或HAND全基因组显著性阈值（5.0×10 ）的单核苷酸多态性（SNP）。对于二元GDS，最显著的SNP是rs6542826（P = 8.1×10 ）和rs11681615（1.2×10 ），均位于2号染色体上的SH3RF3。对于连续GDS，最显著的SNP是位于14号染色体上T细胞受体α位点的rs11157436（P = 1.3×10 ）；该基因中的其他三个SNP也与二元GDS相关（P≤2.9×10 ）。这项在来自单一队列且具有强大神经表型分析的ART时代参与者中进行的GWAS表明，HAND中几个生物学上合理的基因座具有一定作用，值得进一步探索。©2017威利期刊公司
