You are here
IDENTIFICATION OF A NOVEL LOCUS OF HIV REGULATION IN POPULATIONS OF AFRICAN DESCENT
Paul J. McLaren1, Deepti Gurdassani2, Manj Sandhu2, Jacques Fellay3
1Public Health Agency of Canada, Winnipeg, MB, Canada,2Wellcome Trust Sanger Institute, Hinxton, UK,3École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
HIV set point viral load (spVL; log10 RNA copies/ml) strongly correlates with progression and transmission. Genome-wide association studies have shown that ~25% of the variability in spVL is due to host genetics, with the HLA and CCR5 regions being the primary drivers. However, previous studies have focused on individuals of European ancestry, thus assessing only a fraction of human genetic variation. We sought to address this gap by performing a genetic study of spVL in a large sample of individuals of African ancestry.
A discovery set of 2,517 African American individuals with genome-wide genotyping and spVL data was obtained from four independent studies through the International Collaboration for the Genomics of HIV. As a replication sample, we accessed genome-wide data for 533 individuals from 3 studies in eastern and southern Africa and performed direct genotyping in 117 individuals of African descent living in Switzerland (Ncombined=3,167). Association was tested between spVL and genetic variants by linear regression. Discovery and replication results were combined by meta-analysis. Bioinformatic analysis included variant annotation for modification of protein function and gene expression.
In the discovery sample, we observed a novel association between spVL and rs77029719 (p=5.7x10-8; β=-0.30) which was confirmed in the replication set (Pcombined=7x10-10 ; βcombined=-0.31). The effect of rs77029719 was remarkably consistent across populations, with the G allele associating with lower spVL in all groups (range = -0.2 to -0.5 log10(copies/ml)). This variant being located on chromosome 1, this association cannot be explained by the known effects of HLA (chr6) or CCR5 (chr3). rs77029719 falls within a lincRNA and shows strong linkage (r2 > 0.6) with several variants across four genes (CHD1L, FMO5, PDIA3P, PRKAB2). Bioinformatic analysis suggests that rs77029719 plays a role in regulating splicing and expression of CHD1L, which encodes a DNA helicase protein that interacts with PARP1, an enzyme implicated in HIV integration. Interestingly, rs77029719 is only present in populations of African descent, suggesting a population-specific mechanism of HIV control.
We identified an African specific genetic locus that controls HIV replication in vivo with a potential role in modulating HIV integration. These findings suggest a potential new target for anti-HIV drug development and demonstrate the critical need to perform genetic studies in multiple populations.