Identification of Genes Whose Expression Profile Is Associated with Non-Progression towards AIDS Using eQTLs

Abstract

BackgroundMany genome-wide association studies have been performed on progression towards the acquired immune deficiency syndrome (AIDS) and they mainly identified associations within the HLA loci. In this study, we demonstrate that the integration of biological information, namely gene expression data, can enhance the sensitivity of genetic studies to unravel new genetic associations relevant to AIDS.MethodsWe collated the biological information compiled from three databases of expression quantitative trait loci (eQTLs) involved in cells of the immune system. We derived a list of single nucleotide polymorphisms (SNPs) that are functional in that they correlate with differential expression of genes in at least two of the databases. We tested the association of those SNPs with AIDS progression in two cohorts, GRIV and ACS. Tests on permuted phenotypes of the GRIV and ACS cohorts or on randomised sets of equivalent SNPs allowed us to assess the statistical robustness of this method and to estimate the true positive rate.ResultsEight genes were identified with high confidence (p = 0.001, rate of true positives 75%). Some of those genes had previously been linked with HIV infection. Notably, ENTPD4 belongs to the same family as CD39, whose expression has already been associated with AIDS progression; while DNAJB12 is part of the HSP90 pathway, which is involved in the control of HIV latency. Our study also drew our attention to lesser-known functions such as mitochondrial ribosomal proteins and a zinc finger protein, ZFP57, which could be central to the effectiveness of HIV infection. Interestingly, for six out of those eight genes, down-regulation is associated with non-progression, which makes them appealing targets to develop drugs against HIV.

Cellular Proteo-Transcriptomic Changes in the Immediate Early-Phase of Lentiviral Transduction

“…Lastly, TCP1 chaperon complex member 8 (CCT8) was found to be an important marker for disease progression towards AIDS, showing low expression during slow/nonprogression, and increasing correspondingly in AIDS [77]. Moreover, TCP1 is able to interact with the HIV accessory protein Vif.…”

Polymorphisms in mitochondrial ribosomal protein S5 (MRPS5) are associated with leprosy risk in Chinese

“…As yet no studies have reported an association between rs200730619 and disease risk. It has been suggested that mitochondrial ribosomal proteins (MRPs) could be central to the effectiveness of HIV infection [ 51 ], and expression of MRPs was increased in dengue shock syndrome patients [ 52 ]. Moreover, several MRPs were involved in inflammatory and oxidative responses induced by Candida albicans [ 53 ].…”

Large-Scale “OMICS” Studies to Explore the Physiopatholgy of HIV-1 Infection

“…In light of the available biological information provided by the other large-scale studies such as transcriptomic or functional genomic studies presented in this review, it appears important to reanalyze the genomic data by integrating biological information in order to enhance the genetic association results. For instance, our group has successfully implemented such approaches by pre-selecting relevant SNPs defined either by their low frequency (Le Clerc et al, 2011) or by their functional impact as potential expression quantitative trait loci (eQTLs) (Spadoni et al, 2015). More generally, there are several methods for data integration, the first one being to cross-check the results obtained by one method through another, for instance, using GWAS to identify SNPs with low P-values, even non-significant, and then using transcriptomics to pick genes that are differentially expressed in a relevant cell type or tissue.…”