Supplementary MaterialsS1 File: Supporting Results. to unravel new genetic associations relevant

Supplementary MaterialsS1 File: Supporting Results. to unravel new genetic associations relevant to AIDS. Methods We 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 Camptothecin ic50 to assess the statistical robustness of this method and to estimate the true positive rate. Results Eight genes had been determined with high self-confidence (= 0.001, Mouse monoclonal antibody to Rab4 rate of accurate positives 75%). Some of these genes have been associated with HIV disease previously. Notably, is one of the same family members as can be area of the HSP90 pathway, which can be mixed up in control of HIV latency. Our research also drew our focus on lesser-known functions such as for example mitochondrial ribosomal protein and a zinc finger proteins, ZFP57, that could become central to the potency of HIV disease. Oddly enough, for six out of those eight genes, down-regulation is associated with non-progression, which makes them appealing targets to develop drugs against HIV. Introduction More than fifteen genome-wide association studies (GWAS) have been conducted on AIDS since the seminal GWAS on HIV-1 progression in 2007 [1,2]. They mainly revealed associations in the region of the chromosome 6 loci [1,3,4], in particular a single nucleotide polymorphism (SNP) in the gene, rs2395029. This SNP is in complete linkage disequilibrium with the allele, already identified by several candidate-gene studies for its role in non-progression and the control of viral load [5C7]. Candidate gene studies also contributed to the discovery of another important polymorphisms, [8C10]. Most of the genetic association studies on AIDS have relied on endpoints such as viral load at setpoint or time to reach a clinical symptom (e.g. CDC AIDS 1993 or death). The Genetics of Resistance to Immunodeficiency Virus (GRIV) cohort, composed of extreme phenotypes, non-progressors [11C13] and rapid progressors [14], is different since it relies on a case-control analysis. For many human traits and diseases including AIDS, a substantial portion of heritability remains unexplained [15,16]. Strategies to increase the number of novel findings are being developed, including rare variants, facilitated by sequencing, or meta-analyses but with limited success to date [17]. Another approach that has received considerable attention is the use of pathway-based association tests that aim to look for an enrichment of associations in sets of genes within the same biological pathway [18C20]. Genetic association studies on AIDS have been described for specific pathways [21], but a systematic pathway analysis has yet to be performed. Increasingly popular, expression quantitative trait loci (eQTLs) quantify the relationship between genetic polymorphisms and gene transcription [22,23]. It has been proposed that eQTL are of the utmost important in the development of pathological traits [24,25]. In the present work, we have developed a novel, general-purpose pipeline based on the use of several eQTL databases as filters to preselect so-called functional SNPs. We used the databases GHS_Express by [26], Gene Expression Analysis Based on Imputed Genotype by [27], and Genevar by the Sanger Institute [28C30]. These databases correlate each SNP with gene expression in a specific cell line. We preselected the SNPs exhibiting the most significant = 10?4 and the additive mode for eQTLs, we obtained a set of 1788 Camptothecin ic50 SNP/gene pairs corresponding to 1706 distinct SNPs and 567 distinct genes. The set Camptothecin ic50 of SNP/gene pairs is constructed of 73 pairs common to all or any three directories, 33 pairs common to Genevar and Cambien just,.