Genome-wide association study of HIV-associated neurocognitive disorder (HAND): A CHARTER group study.
Genome-wide association study of HIV-associated neurocognitive disorder (HAND): A CHARTER group study.
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DOI：
10.1002/ajmg.b.32530
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
CHARTER Study Group
中科院分区：
文献类型：
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作者：
Jia P;Zhao Z;Hulgan T;Bush WS;Samuels DC;Bloss CS;Heaton RK;Ellis RJ;Schork N;Marra CM;Collier AC;Clifford DB;Gelman BB;Sacktor N;Morgello S;Simpson DM;McCutchan JA;Barnholtz-Sloan JS;Franklin DR;Rosario D;Letendre SL;Grant I;Kallianpur AR;CHARTER Study Group
尽管进行了联合抗逆转录病毒治疗 (ART)，但 HIV 相关神经认知障碍 (HAND) 往往会使 HIV 感染复杂化，并且可能受到宿主基因组学的影响。我们对 1,050 名 CNS HIV 抗逆转录病毒治疗效果研究 (CHARTER) 研究参与者进行了 HAND 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，以确定他们是否患有全球缺陷评分 (GDS) 评估的认知障碍，并排除患有可能混淆 HAND 诊断的合并症的个体。神经认知结局包括GDS定义的神经认知障碍（NCI；二元GDS，366例GDS≥0.5和684例对照GDS<0.5，GDS作为连续变量）和Frascati HAND定义，其中通过自我报告和基于表现的标准评估功能障碍。使用 Affymetrix Human SNP Array 6.0 平台获得基因型数据。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 结果并未显示 SNP 满足 GDS 定义的 NCI 或 HAND 的全基因组显着性阈值 (5.0×10−8)。对于二元 GDS，最显着的 SNP 是 rs6542826 (p=8.1×10−7) 和 rs11681615 (1.2×10−6)，均位于 SH3RF3 的 2 号染色体上。连续 GDS 最显着的 SNP 是 T 细胞受体 α 基因座中 14 号染色体上的 rs11157436 (p=1.3×10−7)；该基因中的其他三个 SNP 也与二元 GDS 相关（p≤2.9×10−6）。这项 GWAS 是在来自具有强大神经学表型的单一队列的 ART 时代参与者中进行的，表明 HAND 中几个生物学上合理的位点的作用值得进一步探索。
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 was 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 (5.0×10−8) for GDS-defined NCI or HAND. For binary GDS, the most significant SNPs were rs6542826 (p=8.1×10−7) and rs11681615 (1.2×10−6), both located on chromosome 2 in SH3RF3. The most significant SNP for continuous GDS was rs11157436 (p=1.3×10−7) on chromosome 14 in the T-cell-receptor alpha locus; three other SNPs in this gene were also associated with binary GDS (p≤2.9×10−6). 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.