High density genotyping for immunogenetic polymorphisms associated with transmission and control of HIV-1 infection in Zambian heterosexual serodiscordant couples.

摘要

Understanding host genetic correlates of HIV-1 outcomes in sub-Saharan African populations is of continued importance due to the disproportionate disease burden in this population. We sought to identify genetic variants associated with HIV-1 acquisition in a sample of 439 initially seronegative individuals enrolled in the Zambia-Emory HIV Research Project, as well as novel variants associated with viral load (VL) in a sample of 172 seroconverters (SCs) with an estimated date of infection and 449 seroprevalent individuals (SPs).;We were unable to detect any statistically significant associations in our analysis of HIV-1 acquisition, though one signal in the HLA-DOA gene associated with accelerated time-to-transmission (rs592625) approached significance at a p value threshold of 2.8×10 -5 (HR=1.6, p=4.0×10-4). We observed a signal in the NOTCH4 gene (rs3134931) and increased set-point VL in SCs that was consistent with two prior studies. Furthermore, rs2857114 in the HLA-DOB gene was associated with increased VL in SPs. We also identified several novel variants and haplotypes within the IL10 gene cluster on chromosome 1 associated with both set-point VL and chronic VL. None of these novel associations in the IL10 gene cluster were statistically significant after accounting for multiple testing. We were able to confirm a number of prior reported associations in other populations in our analysis of SCs, including three variants intergenic between IL20 and IL24: rs1518108 (β=-0.19, p=0.010), rs4845147 (β=-0.17, p=0.029), and rs6540701 (β=-0.17, p=0.025).;This dissertation demonstrates the value of a targeted genotyping platform designed for fine-mapping and replication in the discovery of novel genetic signals for three different HIV-1 phenotypes. If confirmed, associations reported here within the NOTCH4 and the HLA-DO genes may warrant further investigation in the search for genetically informed therapies that could help to prevent HIV-1 infection or help to treat the disease after infection.