Multiple-cohort genetic association study reveals CXCR6 as a new chemokine receptor involved in long-term nonprogression to AIDS

• Published in: The Journal of infectious diseases Vol. 202; no. 6; pp. 908 - 915
• Main Authors: Limou, Sophie, Coulonges, Cédric, Herbeck, Joshua T., van Manen, Daniëlle, An, Ping, Le Clerc, Sigrid, Delaneau, Olivier, Diop, Gora, Taing, Lieng, Montes, Matthieu, van't Wout, Angélique B., Gottlieb, Geoffrey S., Therwath, Amu, Rouzioux, Christine, Delfraissy, Jean-François, Lelièvre, Jean-Daniel, Lévy, Yves, Hercberg, Serge, Dina, Christian, Phair, John, Donfield, Sharyne, Goedert, James J., Buchbinder, Susan, Estaquier, Jérôme, Schächter, François, Gut, Ivo, Froguel, Philippe, Mullins, James I., Schuitemaker, Hanneke, Winkler, Cheryl, Zagury, Jean-François
• Format: Journal Article
• Language: English
• Published: Oxford University Chicago Press 15.09.2010; University of Chicago Press; Oxford University Press
• Subjects: Acquired Immunodeficiency Syndrome - genetics; Acquired Immunodeficiency Syndrome - immunology; AIDS; Biological and medical sciences; Cohort Studies; Computer software; Genetic Association Studies; Genomics; Haplotypes; HIV 1; HIV Long-Term Survivors; HIV/AIDS; Human genetics; Human viral diseases; Humans; Immunity, Innate; Infections; Infectious diseases; Major and Brief Reports; Male; Medical genetics; Medical sciences; Polymorphism, Genetic; Receptors, Chemokine - genetics; Receptors, Chemokine - immunology; Receptors, CXCR6; Receptors, Virus - genetics; Receptors, Virus - immunology; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral load; Infection; Immunopathology; Viral disease; Cohort study; AIDS; Chemokine receptor; Immune deficiency
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1086/655782

Background. The compilation of previous genomewide association studies of AIDS shows a major polymorphism in the HCP5 gene associated with both control of the viral load and long-term nonprogression (LTNP) to AIDS. Methods. To look for genetic variants that affect LTNP without necessary control of the viral load, we reanalyzed the genomewide data of the unique LTNP Genomics of Resistance to Immunodeficiency Virus (GRIV) cohort by excluding “elite controller” patients, who were controlling the viral load at very low levels (<100 copies/mL). Results. The rs2234358 polymorphism in the CXCR6 gene was the strongest signal (P = 2.5 × 10−7; odds ratio, 1.85) obtained for the genomewide association study comparing the 186 GRIV LTNPs who were not elite controllers with 697 uninfected control subjects. This association was replicated in 3 additional independent European studies, reaching genomewide significance of Pcombined = 9.7 × 10−10. This association with LTNP is independent of the combined CCR2-CCR5 locus and the HCP5 polymorphisms. Conclusion. The statistical significance, the replication, and the magnitude of the association demonstrate that CXCR6 is likely involved in the molecular etiology of AIDS and, in particular, in LTNP, emphasizing the power of extreme-phenotype cohorts. CXCR6 is a chemokine receptor that is known as a minor coreceptor in human immunodeficiency virus type 1 infection but could participate in disease progression through its role as a mediator of inflammation.