Immunogenetic influences on acquisition of HIV-1 infection: consensus findings from two African cohorts point to an enhancer element in IL19 (1q32.2)

Abstract

Numerous reports have suggested that immunogenetic factors may influence HIV-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20, and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single nucleotide polymorphisms (SNPs) passed quality control procedures. When HIV-1-exposed seronegative subjects (n = 486) were compared with newly seroconverted individuals (n = 313) and seroprevalent subjects (n = 478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio = 0.64, P = 1.7 × 10−4, and q = 0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.

Immunogenetic determinants of heterosexual HIV-1 transmission: key findings and lessons from two distinct African cohorts

“…The availability of high-throughput assays, including next-generation sequencing and SNP arrays (the ImmunoChip), broadened the search to genome-wide signals or specific gene clusters (e.g., those encoding killer cell immunoglobulin-like receptors/KIRs) that are not adequately covered by other genotyping platforms. In particular, fine-mapping for hundreds of immune response genes was made possible by the ImmunoChip bead arrays (versions 1 and 2) [ 39 – 41 ], although the actual coverage for signal-rich regions (e.g., MHC) remained suboptimal [ 42 , 43 ]. Occasionally, targeted NGS was able to fill in various gaps through phased allele and haplotype assignments (GenDx, Utrecht, The Netherlands).…”

“…This work used a relatively recent GWAS array (the Illumina Multi-Ethnic Genotyping Array) that is considered suitable for African cohorts [ 58 ] and covers over 1.5 million SNPs, with extra flexibility for accommodating up to 300,000 custom SNPs. In a more focused screening facilitated by two versions of the Illumina ImmunoChip, which is cost-effective and targets a broad range of SNPs mapped to genes that mediate innate and adaptive immune responses [ 43 ], ~195,000 ImmunoChip version 1 SNPs passed various quality control measures and were deemed acceptable for association analyses – a discovery phase (in the larger Zambian cohort) was followed by a validation phase (in the smaller Rwandan cohort). Again, not a single SNP met the typical, minimal level of study-wide statistical significance ( P <0.05 in both cohorts, after Bonferroni correction for the number of independent tests).…”

“…In other applications, genomics data proved useful in determining biological sex, cryptic familial relatedness (kinship) and genetic outliers [ 43 ]. In addition, Many SNPs in the extended MHC region helped with the fine-mapping of association signals detected for individual HLA alleles or amino acid residues [9).…”