Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 47; pp. 14658 - 14663
• Main Authors: McLaren, Paul J., Coulonges, Cedric, Bartha, István, Lenz, Tobias L., Deutsch, Aaron J., Bashirova, Arman, Buchbinder, Susan, Carrington, Mary N., Cossarizza, Andrea, Dalmau, Judith, De Luca, Andrea, Goedert, James J., Gurdasani, Deepti, Haas, David W., Herbeck, Joshua T., Johnson, Eric O., Kirk, Gregory D., Lambotte, Olivier, Luo, Ma, Mallal, Simon, van Manen, Daniëlle, Martinez-Picado, Javier, Meyer, Laurence, Miro, José M., Mullins, James I., Obel, Niels, Poli, Guido, Sandhu, Manjinder S., Schuitemaker, Hanneke, Shea, Patrick R., Theodorou, Ioannis, Walker, Bruce D., Weintrob, Amy C., Winkler, Cheryl A., Wolinsky, Steven M., Raychaudhuri, Soumya, Goldstein, David B., Telenti, Amalio, de Bakker, Paul I. W., Zagury, Jean-François, Fellay, Jacques
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.11.2015; National Acad Sciences
• Subjects: Adult; Alleles; Amino acids; Amino Acids - genetics; Biological Sciences; Chemokines; Chromosomes; Chromosomes, Human, Pair 3 - genetics; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomes; Genotype & phenotype; HIV; HIV-1 - genetics; HLA-B Antigens - genetics; Host-Pathogen Interactions - genetics; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Inheritance Patterns - genetics; Physical Chromosome Mapping; Polymorphism, Single Nucleotide - genetics; Proteins; Receptors, CCR5 - genetics; Viral Load - genetics; genomics; GWAS; HIV-1 control; infectious disease; heritability
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1514867112

Previous genome-wide association 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 European ancestry. The strongest signal 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 analysis showed that this signal could not be fully attributed to the known protectiveCCR5Δ32allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic 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.