Common genetic variation and the control of HIV-1 in humans.
Common genetic variation and the control of HIV-1 in humans.
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DOI：
10.1371/journal.pgen.1000791
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
中科院分区：
文献类型：
--
作者：
Fellay J;Ge D;Shianna KV;Colombo S;Ledergerber B;Cirulli ET;Urban TJ;Zhang K;Gumbs CE;Smith JP;Castagna A;Cozzi-Lepri A;De Luca A;Easterbrook P;Günthard HF;Mallal S;Mussini C;Dalmau J;Martinez-Picado J;Miro JM;Obel N;Wolinsky SM;Martinson JJ;Detels R;Margolick JB;Jacobson LP;Descombes P;Antonarakis SE;Beckmann JS;O'Brien SJ;Letvin NL;McMichael AJ;Haynes BF;Carrington M;Feng S;Telenti A;Goldstein DB;NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)
为了扩展对HIV-1控制的宿主遗传决定因素的理解，我们在2，554名感染的高加索受试者的队列中进行了全基因组关联研究。该研究有能力检测常见的遗传变异，解释设定点病毒载量变异的1.3%。我们对先前在全基因组研究中报道的三种关联提供了压倒性的确认，并显示了主要组织相容性复合体区域（MHC）中常见和罕见变异的进一步独立影响。我们还检查了以前的候选基因研究中报道的多态性，并未能支持任何MHC或3号染色体上趋化因子受体簇以外的变体的作用。此外，我们还评估了功能变异、拷贝数多态性、上位相互作用和生物学途径。因此，这项研究代表了一个全面的评估共同的人类遗传变异的HIV-1控制在高加索人。感染后自发控制HIV-1的能力在个体之间差异很大。为了评估人类基因变异对血浆病毒载量和疾病进展率差异的贡献，我们在> 2，500名HIV感染者中进行了全基因组关联研究。本研究实现了两个目标：它完成了对影响病毒控制的常见变异的分析，并重新评估了以前报告的大多数遗传关联。我们发现，位于HLA-B和HLA-C基因附近的遗传变异是病毒控制的最强决定因素，其他独立的关联存在于6号染色体的同一区域，即已知含有大量参与免疫防御的基因的主要组织相容性复合体。我们无法在这个大型的、特征明确的队列中复制大多数先前发表的与HIV候选基因的关联。总的来说，常见的人类遗传变异，加上人口统计学变量，解释了高达22%的高加索人群中的病毒载量的变异。
To extend the understanding of host genetic determinants of HIV-1 control, we performed a genome-wide association study in a cohort of 2,554 infected Caucasian subjects. The study was powered to detect common genetic variants explaining down to 1.3% of the variability in viral load at set point. We provide overwhelming confirmation of three associations previously reported in a genome-wide study and show further independent effects of both common and rare variants in the Major Histocompatibility Complex region (MHC). We also examined the polymorphisms reported in previous candidate gene studies and fail to support a role for any variant outside of the MHC or the chemokine receptor cluster on chromosome 3. In addition, we evaluated functional variants, copy-number polymorphisms, epistatic interactions, and biological pathways. This study thus represents a comprehensive assessment of common human genetic variation in HIV-1 control in Caucasians. The ability to spontaneously control HIV-1 upon infection is highly variable between individuals. To evaluate the contribution of variation in human genes to differences in plasma viral load and in disease progression rates, we performed a genome-wide association study in >2,500 HIV–infected individuals. This study achieved two goals: it completed the analysis of common variation influencing viral control, and it re-assessed the majority of previously reported genetic associations. We show that genetic variants located near the HLA-B and HLA-C genes are the strongest determinants of viral control, and that other independent associations exist in the same region of chromosome 6, the Major Histocompatibility Complex, known to contain a large number of genes involved in immune defense. We could not replicate most of the previously published associations with HIV candidate genes in this large, well-characterized cohort. Overall, common human genetic variation, together with demographic variables, explains up to 22% of the variability in viral load in the Caucasian population.
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