McLaren, Paul J2; Coulonges, Cédric2; Ripke, Stephan2; van den Berg, Leonard2; Buchbinder, Susan2; Carrington, Mary2; Cossarizza, Andrea2; Dalmau, Judith2; Deeks, Steven G2; Delaneau, Olivier2; De Luca, Andrea2; Goedert, James J2; Haas, David2; Herbeck, Joshua T2; Kathiresan, Sekar2; Kirk, Gregory D2; Lambotte, Olivier2; Luo, Ma2; Mallal, Simon2; van Manen, Daniëlle2; Martinez-Picado, Javier2; Meyer, Laurence2; Miro, José M2; Mullins, James I2; Obel, Niels4; O'Brien, Stephen J2; Pereyra, Florencia2; Plummer, Francis A2; Poli, Guido2; Qi, Ying2; Rucart, Pierre2; Sandhu, Manj S2; Shea, Patrick R2; Schuitemaker, Hanneke2; Theodorou, Ioannis2; Vannberg, Fredrik2; Veldink, Jan2; Walker, Bruce D2; Weintrob, Amy2; Winkler, Cheryl A2; Wolinsky, Steven2; Telenti, Amalio2; Goldstein, David B2; de Bakker, Paul I W2; Zagury, Jean-François2; Fellay, Jacques2
1 Section of Orthopaedics and Internal Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet4 Department of Clinical Medicine, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10(-11)). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
P L O S Pathogens (online), 2013, Vol 9, Issue 7
Journal Article; Meta-Analysis; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't