Genomewide Association Study of a Rapid Progression Cohort Identifies New Susceptibility Alleles for AIDS (ANRS Genomewide Association Study 03)

Sigrid Le Clerc, Sophie Limou, Cédric Coulonges, Wassila Carpentier, Christian Dina, Lieng Taing, Olivier Delaneau, Taoufik Labib, Rob Sladek, Anrs Genomic Group, Christiane Deveau, Hélène Guillemain, Rojo Ratsimandresy, Matthieu Montes, Jean Louis Spadoni, Amu Therwath, François Schächter, Fumihiko Matsuda, Ivo Gut, Jean Daniel Le LièvreYves Lévy, Philippe Froguel, Jean François Delfraissy, Serge Hercberg, Jean François Zagury*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Background. Previous genomewide association studies (GWASs) of AIDS have targeted end points based on the control of viral load and disease nonprogression. The discovery of genetic factors that predispose individuals to rapid progression to AIDS should also reveal new insights into the molecular etiology of the pathology. Methods. We undertook a case-control GWAS of a unique cohort of 85 human immunodeficiency virus type 1 (HIV-l)-infected patients who experienced rapid disease progression, using Illumina HumanHap300 BeadChips. The case group was compared with a control group of 1352 individuals for the 291,119 autosomal single-nucleotide polymorphisms (SNPs) passing the quality control tests, using the false-discovery rate (FDR) statistical method for multitest correction. Results. Novel associations with rapid progression (FDR, =≤25%) were identified for PRMT6 (P = 6.1 X 10-7; odds ratio [OR], 0.24), SOX5 (P = 1.8 X 10-6; OR, 0.45), RXRG (P = 3.9 X 10 -6; OR, 3.29), and TGFBRAP1 (P = 7 X 10-6; OR, 0.34). The haplotype analysis identified exonic and promoter SNPs potentially important for PRMT6 and TGFBRAP1 function. Conclusions. The statistical and biological relevance of these associations and their high ORs underscore the power of extreme phenotypes for GWASs, even with a modest sample size. These genetic results emphasize the role of the transforming growth factor β pathway in the pathogenesis of HIV-1 disease. Finally, the wealth of information provided by this study should help unravel new diagnostic and therapeutic targets.

Original languageEnglish (US)
Pages (from-to)1194-1201
Number of pages8
JournalJournal of Infectious Diseases
Volume200
Issue number8
DOIs
StatePublished - Oct 15 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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