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Screening Low-Frequency SNPS From Genome-Wide Association Study Reveals a New Risk Allele for Progression to AIDS

Clerc, Sigrid Le PhD; Coulonges, Cédric MS; Delaneau, Olivier PhD; Manen, Danielle Van MS; Herbeck, Joshua T PhD; Limou, Sophie PhD; An, Ping PhD; Martinson, Jeremy J MD; Spadoni, Jean-Louis PhD; Therwath, Amu PhD; Veldink, Jan H PhD; van den Berg, Leonard H PhD; Taing, Lieng MS; Labib, Taoufik MS; Mellak, Safa; Montes, Matthieu PhD; Delfraissy, Jean-François MD, PhD; Schächter, François PhD; Winkler, Cheryl PhD; Froguel, Philippe MD, PhD; Mullins, James I PhD; Schuitemaker, Hanneke PhD; Zagury, Jean-François MD, PhD

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1st, 2011 - Volume 56 - Issue 3 - p 279-284
doi: 10.1097/QAI.0b013e318204982b
Epidemiology and Prevention

Background: Seven genome-wide association studies (GWAS) have been published in AIDS, and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance.

Methods: We reanalyzed the data from 3 previously published GWAS, targeting specifically low-frequency SNPs (minor allele frequency <5%). Two groups composed of 365 slow progressors and 147 rapid progressors from Europe and the United States were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections.

Results: Of the 8584 SNPs with minor allele frequency <5% in cases and controls (Bonferroni threshold = 5.8 × 10−6), 4 SNPs showed statistical evidence of association with the slow progressor phenotype. The best result was for HCP5 rs2395029 [P = 8.54 × 10−15, odds ratio (OR) = 3.41] in the HLA locus, in partial linkage disequilibrium with 2 additional chromosome 6 associations in C6orf48 (P = 3.03 × 10−10, OR = 2.9) and NOTCH4 (9.08 × 10−07, OR = 2.32). The fourth association corresponded to rs2072255 located in RICH2 (P = 3.30 × 10−06, OR = 0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant.

Conclusions: Besides the already known chromosome 6 associations, the analysis of low-frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low-frequency SNPs to exploit GWAS data.

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From the *Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France; †Université Paris, INSERM U955, Créteil, France; ‡ANRS Genomic Group (French Agency for Research on AIDS and Hepatitis), Paris, France; §Department of Experimental Immunology, Sanquin Research, Landsteiner Laboratory, Center for Infectious Diseases and Immunity Amsterdam Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; ‖Department of Microbiology, University of Washington School of Medicine, Seattle, WA; ¶CEA/Institut de Génomique, Centre National de Génotypage, Evry, France; #Laboratory of Genomic Diversity, SAIC-Frederick, Inc, National Cancer Institute-Frederick, Frederick, MD; **Department of Human Genetics University of Pittsburgh, Pittsburgh, PA; ††Laboratoire d'Oncologie Moléculaire, Université Paris, Paris, France; ‡‡Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands; §§UMR CNRS 8090, Institut Pasteur de Lille, Lille, France; and ‖‖Genomic Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom.

Received for publication August 18, 2010; accepted October 20, 2010.

Supported by Agence Nationale de Recherche sur le SIDA (ANRS), Sidaction, Fondation de France, Innovation 2007 program of Conservatoire National des Arts et Métiers (CNAM), AIDS Cancer Vaccine Development Foundation, Neovacs SA, Vaxconsulting. Sophie Limou benefits from a fellowship from the French Ministry of Education, Technology and Research and Sigrid Le Clerc benefits from a fellowship of ANRS. The Amsterdam Cohort Studies on HIV infection and AIDS, a collaboration between the Amsterdam Health Service, the Academic Medical Center of the University of Amsterdam, Sanquin Research, and the University Medical Center Utrecht, are part of the Netherlands HIV Monitoring Foundation and financially supported by the Netherlands National Institute for Public Health and the Environment. The authors acknowledge funding from the Netherlands Organization for Scientific Research (TOP, registration number 9120.6046). The MultiCenter AIDS Cohort Study is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute. UO1-AI-35042, UL1-RR025005 (GCRC), UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041. This project has been funded in part with federal funds from the National Institutes of Health, under contract HHSN261200800001E. This Research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

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Correspondence to: Jean-François Zagury, MD, PhD, 292 rue Saint Martin, 75003 Paris, France (e-mail:

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