Joining Forces in HIV Host Genomics: The International HIV Acquisition Consortium
Paul McLaren*1, J-F Zagury2, J Fellay3, and the Intl HIV Acquisition Consortium
1Brigham and Women`s Hosp and Broad Inst of MIT and Harvard, Boston, MA, US; 2Conservatoire Natl des Arts et Métiers, Paris, France; and 3Federal Inst of Tech, Lausanne, Switzerland
Background: The International HIV Acquisition Consortium (IHAC) was established in 2009 as a collaborative effort between scientists and institutions working in HIV host genetics. By combining genome-wide genotype data from multiple cohorts of HIV-infected individuals and comparing them to large numbers of uninfected population controls, IHAC aims at greatly enhancing the power to identify genetic variants that could lead to additional insight into the HIV transmission event and drive novel intervention strategies.
Methods: Existing genome-wide genotype data were obtained from HIV-infected and population-based uninfected cohorts. HIV infected and uninfected individuals were matched based on genotyping platform and principal components informed by genome-wide association study (GWAS) data, resulting in 6 sample groups. Per group, untyped single nucleotide polymorphisms (SNP) were imputed using 1000 Genomes Project data as a reference panel and association was tested using logistic regression including principal components to correct for population structure. Association results were then meta-analyzed across sample groups.
Results: A total of 9978 HIV-infected cases and 9504 HIV-uninfected controls were recruited for analysis of common genetic influences on HIV susceptibility. Initial analysis focused on 6556 HIV-1-infected cases and 7253 HIV-uninfected controls of European ancestry. After imputation, ~12 million SNP were available for association testing. Genome-wide significant signals were only observed in the class I HLA region of the major histocompatibility complex (MHC) on chromosome 6. The strongest associated variant (p = 9.34x10–11) was rs4418214, a tagging SNP for HLA alleles B*57:01 and B*27:05, known to associate with better control of HIV and longer survival in infected individuals, and thus expected to be enriched in chronically infected populations. Sensitivity analyses confirmed that the MHC signals were augmented in sample groups including larger numbers of HIV controllers.
Conclusions: The largest GWAS performed on data from HIV cohorts did not identify novel common host genetic determinants of HIV susceptibility. Similar investigations in individuals of African ancestry are ongoing. Additional contributors are always welcome to join the Consortium: upcoming analyses will focus on HIV control phenotypes.