Common genetic variation and the control of HIV-1 in humans

Abstract

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.

Figure 1. Significant hits in the MHC region.

Representation of a 3 Mb stretch in the MHC region, encompassing the HLA Class I gene loci and the genome-wide significant SNPs identified in the study (red dots represents SNPs with p-value<5E–08). Results are shown for set point (upper plot) and for progression (lower plot). The figure was created with WGAViewer .

Figure 2. Correlation between HIV-1 set point and the genotypes of the top associated SNPs.

HIV-1 viremia at set point strongly associates with rs2395029 (upper panel) and rs9264942 (lower panel) genotypes. The rs2395029 minor allele G has a frequency of 4.8% and each copy of this allele associates with a 0.7 log lower set point. The rs9264942 minor allele C has a frequency of 41.2%, and each copy of this allele associates with a 0.3 log lower set point. Mean and Standard Deviation (error bars) are represented for the respective genotypes.

Figure 3. Kaplan-Meier survival estimates for the top associated variants.

Results are shown for the 3 most associated SNPs indentified in the genome-wide progression scan and for CCR5-Δ32. The survival curves show, for each genotype, the proportion of the individuals that do not reach a progression outcome over the first 10 years after seroconversion.

Figure 4. Allelic distribution of the significant variants in subsets of the study population.

The bar graphs show the allelic distribution of the 4 variants that have a genome-wide significant association with HIV-1 set point and/or disease progression in subsets of the study population. Groups were defined according to HIV-1 set point (left-hand side graphs) and to progression time (right-hand side graphs).