Multistage genomewide association study identifies a locus at 1q41 associated with rate of HIV-1 disease progression to clinical AIDS

Abstract

Background: A mean of 9-10 years of human immunodeficiency virus type 1 (HIV-1) infection elapse before clinical AIDS develops in untreated persons, but this rate of disease progression varies substantially among individuals. To investigate host genetic determinants of the rate of progression to clinical AIDS, we performed a multistage genomewide association study.

Methods: The discovery stage comprised 156 individuals from the Multicenter AIDS Cohort Study, enriched with rapid and long-term nonprogressors to increase statistical power. This was followed by replication tests of putatively associated genotypes in an independent population of 590 HIV-1-infected seroconverters.

Results: Significant associations with delayed AIDS progression were observed in a haplotype located at 1q41, 36 kb upstream of PROX1 on chromosome 1 (relative hazard ratio, 0.69; Fisher's combined P = 6.23 X 10(-7)). This association was replicated further in an analysis stratified by transmission mode, with the effect consistent in sexual or mucosal and parenteral transmission (relative hazard ratios, 0.72 and 0.63, respectively; combined P = 1.63 X 10(-6)).

Conclusions: This study identified and replicated a locus upstream of PROX1 that is associated with delayed progression to clinical AIDS. PROX1 is a negative regulator of interferon-gamma expression in T cells and also mitigates the advancement of vascular neoplasms, such as Kaposi sarcoma, a common AIDS-defining malignancy. This study adds to the cumulative polygenic host component that effectively regulates the progression to clinical AIDS among HIV-1-infected individuals, raising prospects for potential new avenues for therapy and improvements in AIDS prognosis.

Figure 1

Survival analysis of a locus associated with delayed progression to AIDS. Kaplan-Meier survival curves for genotypes of single-nucleotide polymorphism rs17762192, representing a haplotype located 36 kb upstream of PROX1 on chromosome 1, showing strong associations with differing rates of progression to clinical AIDS (see Table 3 for P values and genomic location). This analysis incorporates seroconverters from the stage 2 replication analysis that were typed for rs17762192 (n = 587). GG, GC, and CC genotype counts are shown for the independent replication cohort (A) and the independent replication cohort combined with the cohort used in the stage 1 discovery genomewide association study (B). RH, relative hazard.

Figure 2

Location of the 3 single-nucleotide polymorphisms (SNPs) in the upstream region of the PROX1 gene (1q32) and linkage disequilibrium matrix; the linkage disequilibrium matrix was shown by Haploview for the HapMap Utah European population. The intensity of the red color in each box is proportional to the strength of the linkage disequilibrium estimates (D′) for the SNP pair. Linkage disequilibrium blocks depicted by black triangles were based on 95% confidence interval criteria [34].