Research Article: Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls

Date Published: July 25, 2013

Publisher: Public Library of Science

Author(s): Paul J. McLaren, Cédric Coulonges, Stephan Ripke, Leonard van den Berg, Susan Buchbinder, Mary Carrington, Andrea Cossarizza, Judith Dalmau, Steven G. Deeks, Olivier Delaneau, Andrea De Luca, James J. Goedert, David Haas, Joshua T. Herbeck, Sekar Kathiresan, Gregory D. Kirk, Olivier Lambotte, Ma Luo, Simon Mallal, Daniëlle van Manen, Javier Martinez-Picado, Laurence Meyer, José M. Miro, James I. Mullins, Niels Obel, Stephen J. O’Brien, Florencia Pereyra, Francis A. Plummer, Guido Poli, Ying Qi, Pierre Rucart, Manj S. Sandhu, Patrick R. Shea, Hanneke Schuitemaker, Ioannis Theodorou, Fredrik Vannberg, Jan Veldink, Bruce D. Walker, Amy Weintrob, Cheryl A. Winkler, Steven Wolinsky, Amalio Telenti, David B. Goldstein, Paul I. W. de Bakker, Jean-François Zagury, Jacques Fellay, François Balloux.

http://doi.org/10.1371/journal.ppat.1003515

Abstract

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.

Partial Text

Variation in infection susceptibility and severity is a hallmark of infectious disease biology. This natural variation can be attributed to a variety of host, pathogen and environmental factors, including host genetics. Several genome-wide association studies (GWAS) of HIV-1 outcomes have been performed primarily to assess the impact of human genetic variation on plasma viral load and/or disease progression [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. These studies have confirmed the key role of major histocompatibility complex (MHC) polymorphisms in HIV-1 control, with a minor impact of variants in the CCR5 gene region.

By assembling a large collaborative network of cohorts and institutions involved in HIV-1 host genetic studies we sought to test for common genetic polymorphisms that influence HIV-1 acquisition. Through this network, we were able to combine genome-wide SNP data on over 6,300 HIV-1 infected patients of European ancestry. In order to maximize power, we further accessed large population-level genotype data sets to use as controls. Where necessary, case/control samples were iteratively matched to limit inflation in the test statistic due to platform or cohort effects. Genome-wide imputation using the 1,000 Genomes Project CEU sample as a reference panel resulted in a set of approximately 8×106 high-quality variants that were tested for association with HIV-1 acquisition. We observed 11 variants that passed the genome-wide significance threshold, all located in the MHC region. Imputation and association testing of the CCR5Δ32 polymorphism demonstrated that this sample size and study design are appropriate to detect strong associations that impact HIV-1 acquisition.

 

Source:

http://doi.org/10.1371/journal.ppat.1003515

 

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