GWAS on Determinants of HIV-1 Subtype C Infection

描述(申请人提供)：研究领域为主题4，重点是全球健康。该项目的广泛目标是确定在南部非洲受艾滋病毒/艾滋病疫情严重影响的人群中艾滋病毒-1 C亚型感染的易感性和抵抗力的决定因素以及疾病进展的决定因素，并通过确定制定新的干预和预防战略的宿主目标来减轻艾滋病毒-C感染的负担。尽管艾滋病毒-1C亚型(HIV-1C)在世界范围内占主导地位，但大多数全基因组关联研究(GWAS)主要是在感染艾滋病毒-1B亚型的欧洲血统男性身上进行的。艾滋病毒的负担在南部非洲最严重，那里的艾滋病毒-1C疫情感染了16%的成年人，其中60%是女性，病毒传播的主要方式是异性。这项拟议的研究是第一次用于获取艾滋病毒-1C和控制病毒复制的GWAS，是第一次在南部非洲人口中进行的GWAS，也是第一次使用新的2.5 Illumina芯片的GWAS。具体目标1：使用Illumina Omni 2.5珠芯片对居住在博茨瓦纳哈博罗内的3,200名艾滋病毒携带者和3,200名艾滋病毒携带者的博茨瓦纳成年人的DNA样本进行GWA。在参加Mochudi HIV治疗预防计划的5,500名HIV+和5,500名HIV-Tswana成年人中，与艾滋病毒感染状况以及病毒载量(VL)和CD4水平的轨迹之间的显著关联将在GWAS中复制。具体目标2：对6个个体的子集使用全基因组30x测序，对77个(均为Gwas)使用代表HIV-1C病毒载量极端表型的外显子组测序，以识别罕见到中等频率的变异。被确定为推定原因的功能性遗传变异将通过关联分析在全套17,400人中与艾滋病毒感染状况有关，并在1,775人中分析VL和CD4+T细胞的轨迹。具体目标3：使用1000基因组计划的结果，HapMap计划的第三阶段，以及我们自己对茨瓦纳人的深度测序，以确定预测艾滋病毒-1C感染状态风险的因果变异，以及VL和CD4+计数的轨迹。基于合并的分析将被用于识别含有因果/功能性SNP的单倍型。推定的因果SNPs将在整个17400人的群体中进行基因分型，以进行关联。这项创新的研究将GWAS与基因组重新测序(30倍)相结合，应用于第一个南部非洲艾滋病毒-1C感染的遗传研究。这是第一次在独立队列中大力复制结果的艾滋病毒全球监测系统。这项研究将确定新的宿主因素，这些因素可能是更好地了解艾滋病毒感染的易感性和抵抗力的目标，以及决定疾病进展速度的因素。 公共卫生相关性：这项研究具有创新性，因为它将Illumina 2.5 GWAS与深度测序相结合，应用于非洲第一个艾滋病毒-1C感染的基因研究--此外，这是第一个支持在独立受试者中强有力地复制和验证结果的HIV Gwas。这项研究具有非常重要的意义，因为它应该确定新的宿主因素，这些因素可能是了解对初始感染的抵抗力的目标，以及决定进展速度的因素。这项研究还将量化宿主遗传因素和非遗传因素对南部非洲当前疫情的相对贡献。

DESCRIPTION (provided by applicant): The research area is theme number 4, Focusing on Global Health. The broad goals of the project are to identify determinants of susceptibility and resistance to infection by HIV-1 subtype C and of disease progression among people severely affected by the HIV/AIDS epidemic in southern Africa, and to reduce the burden of HIV1-C infection by identifying host targets for developing new intervention and prevention strategies. Despite the worldwide predominance of HIV-1 subtype C (HIV-1C), most genome wide association studies (GWAS) have been conducted primarily on males of European ancestry infected by HIV-1 subtype B. The burden of HIV is greatest in southern Africa where the HIV-1C epidemic has infected 16% of adults of whom >60% are women, and the dominant mode of viral transmission is heterosexual. The proposed study represents the first GWAS for HIV-1C acquisition and control of viral replication, the first GWAS in the southern African population, and the first GWAS using the new 2.5 Illumina chip. Specific Aim 1: To perform a GWAS using the Illumina Omni 2.5 BeadChip on DNA samples from 3,200 HIV+ and 3,200 HIV- Tswana adults living in Gaborone, Botswana. Significant associations with HIV infection status and trajectories of viral load (VL) and CD4 levels from the GWAS will be replicated in a group of 5,500 HIV+ and 5,500 HIV- Tswana adults enrolled in the Mochudi HIV Treatment for Prevention Program. Specific Aim 2: To use whole-genome 30x sequencing for a subset of 6 individuals and exome sequencing for 77 (all with GWAS) representing extreme phenotypes for HIV-1C viral load to identify rare-to-moderate frequency variants. Functional genetic variation identified as putatively causal will be analyzed by association analysis in the full set of 17,400 individuals for association with HIV infection status and on 1,775 individuals for trajectories of VL and CD4+ T cells. Specific Aim 3: To use the results of the 1000 Genomes Project, phase three of the HapMap project, and our own deep sequencing of Tswana persons to identify causal variants that predict risk for HIV-1C infection status, and trajectories of VL and CD4+ counts. Coalescence-based analysis will be used to identify haplotypes harboring causal/functional SNPs. Putative causal SNPs will be genotyped on the entire group of 17,400 persons for association. This innovative study applies a GWAS combined with genome re-sequencing (30-fold) to the first southern African genetic study of HIV-1C infection. This is the first HIV GWAS powered for strong replication of results in an independent cohort. This study would identify novel host factors that may be targets for better understanding susceptibility and resistance to HIV infection and factors that determine the rate of disease progression. PUBLIC HEALTH RELEVANCE: This study is innovative in that it applies the Illumina 2.5 GWAS combined with deep sequencing to the first African genetic study of HIV-1C infection-plus this is the first HIV GWAS powered for strong replication and validation of results in independent subjects. This study is highly significant because it should identify novel host factors that may be targets for understanding resistance to initial infection and factors that determine the rate of progression. This study will also quantify the relative contribution of host genetic factors and non-genetic factors to the current epidemic in southern Africa.