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要旨

Previous genome-wide associat ion studies (GWAS) of HIV-1 – infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼ 8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of Eur opean ancestry. The strongest sig- nal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional a nalysis showed that this signal could not be fully attributed to the known protective CCR5 Δ 32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human ge- netic variation — mostly in the HLA and CCR5 regions — explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.