A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A
A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A
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DOI：
10.1093/hmg/ddt033
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发表时间：
2013-05-01
影响因子：
3.5
通讯作者：
Fellay, Jacques
中科院分区：
文献类型：
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作者：
Lane, Jerome;McLaren, Paul J.;Fellay, Jacques
人类遗传变异导致对HIV-1感染易感性的差异。为了寻找新的宿主耐药因子，我们在高度暴露于潜在污染的因子VIII输注的血友病患者中进行了全基因组关联研究（GWAS）。从36个血友病治疗中心（HTC）招募了血友病A患者和在引入病毒灭活程序（1979-1984）之前有记录的因子VIII输注史的患者，并将其全基因组遗传变异与匹配的HIV感染者进行了比较。排除已知CCR 5耐药突变的纯合子携带者。单核苷酸多态性（SNPs）和推断的拷贝数变异（CNVs）进行了测试，使用逻辑回归。此外，我们还进行了途径富集分析、遗传力分析以及与CCR 5 D32杂合性的上位性相互作用研究。共招募了560例HIV未感染病例：36例（6.4）为CCR 5 32或m303纯合子。经过质量控制和SNP插补，我们检测了431例HIV感染者和765例对照中1081435个SNP和3686个CNV与HIV-1血清学状态的相关性。没有SNP或CNV达到全基因组显著性。额外的分析没有发现任何强的遗传效应。高度暴露，但未感染的血友病患者形成了一个理想的研究组，以研究宿主的抗性因素。使用全基因组方法，我们没有检测到SNP与HIV-1易感性之间的任何显着关联，表明主要影响的常见遗传变异不太可能解释在该人群中观察到的耐药表型。
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 D32 heterozygosity.A total of 560 HIV-uninfected cases were recruited: 36 (6.4) were homozygous for CCR5 32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect.Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.