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

Abstract

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 x 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 P(combined)=9.7 x 10(-10). This association with LTNP is independent of the CCR2-CCR5 locus and the HCP5 polymorphisms.

Conclusions: 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.

Figure 1.

Effect of rs2234358 in the Genomics of Resistance to Immunodeficiency Virus (GRIV), Amsterdam Cohort Study (ACS), Multicenter AIDS Cohort Study (MACS), and USA HIV-1 study groups. A, Allelic frequency of rs2234358-T in the GRIV long-term nonprogressor (LTNP) population (n = 186) and the control group (CTR) (n = 697). Frequencies are also given for the 31 ACS subjects with LTNP (ACS LTNPs), for the remaining 285 ACS participants (ACS^*), for the 59 MACS subjects with LTNP (MACS LTNPs), and for the remaining 97 MACS participants (MACS^*). B, Kaplan-Meier survival curve derived from the ACS cohort for the time to AIDS-related death. Genotypes GG (green) (n = 76), GT (blue) (n = 171), and TT (black) (n = 69). C, Kaplan-Meier survival curve derived from the MACS cohort for time to clinical AIDS. Genotypes GG (green) (n = 45), GT (blue) (n = 72), and TT (black) (n = 39). D, Kaplan-Meier survival curve derived from the USA HIV-1 cohort for time to AIDS-related death. Genotypes GG (green) (n = 140), GT (blue) (n = 297), and TT (black) (n = 119).

Figure 2.

A, Genetic map of the CXCR6 gene region. CXCR6 is localized within the 14th intron of a predicted gene, FYCO1. B, Genetic map of the CXCR6 gene. Exons and untranslated regions are symbolized by full and empty rectangles, respectively. The positions of the ATG and STOP codons are indicated by a triangle (▸) and an asterisk (^*), respectively. All single-nucleotide polymorphisms (SNPs) covered by the polymerase chain reaction sequencing study are represented, and the rs2234358 SNP of interest is shown in boldface type. The 3 promoter haplotypes in high linkage disequilibrium (LD) with rs2234358 (r² = 0.97) correspond to 2-SNP haplotypes composed of the rs2234350 SNP (°), with either one of the SNPs denoted by the + symbol (these 3 latter SNPs exhibit r² = 0.99).