Genomewide Association Study of an AIDS‐Nonprogression Cohort Emphasizes the Role Played byHLAGenes (ANRS Genomewide Association Study 02)

Abstract

To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5 rs2395029 (P=6.79x10(-10); odds ratio, 3.47) and was possibly linked to an effect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal (P=3.02x10(-19)) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection.

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

“…Polymorphisms in the ZNRD1 gene remained statistically significantly associated with the LTNP phenotype when HLA-A10 was introduced as a covariable in the analysis. In addition, the effect of HLA-A10 was not statistically significantly associated with progression, suggesting a more discrete effect (if any) and an independent role for ZNRD1, in accordance with the findings of other association studies [7,30,31,37]. Although the earlier studies were based on the complex spatial structure and linkage disequilibrium pattern of a relatively large region, we took a more focused approach on individual polymorphisms around the ZNRD1 gene, because of its demonstrated effect on HIV-1 replication in cell culture.…”

“…In the middle of such an intricate picture, however, several genetic polymorphisms have been described that clearly influence the outcome of HIV infection, specially in the HLA region, where ZNRD1 is located [7,31,36,37]. Genetic complexity and the high linkage disequilibrium of the region challenges the effect of ZNRD1 on HIV disease progression [32,37].…”

Comparative Analysis of the Capacity of Elite Suppressor CD4 + and CD8 + T Cells To Inhibit HIV-1 Replication in Monocyte-Derived Macrophages

“…This idea has long been supported by both functional studies examining the response and quality of ES CD8 ϩ T cells (2, 3, 5, 10, 36-40) and genome-wide association studies identifying major histocompatibility complex class I alleles (such as HLA-B*57 and HLA-B*27) (41)(42)(43)(44)(45)(46). In addition, these protective HLA alleles have been shown to be overrepresented in multiple ES cohorts (5,41,(47)(48)(49)(50)(51)(52).…”

Genetic interplay betweenHLA-CandMIR148Ain HIV control and Crohn disease

“…Genome-wide association studies (GWASs) have shown that variation in HLA class I region has the greatest differential influence on HIV viral load control (17)(18)(19)(20)(21)(22). Delineating the precise "causal" locus/loci, however, is problematic in the rich environment of functionally related, highly polymorphic, and tightly linked disease candidate loci located within the MHC.…”