Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility

Abstract

BackgroundVariability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes.Methodology/Principal FindingsTo get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78×10−12), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9×10−7), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself.Conclusions/SignificanceThis study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment.

Variants at IRX4 as prostate cancer expression quantitative trait loci

“…Lastly, rs7250689 has been previously found to be associated with levels of PPP1R14A in monocytes (eQTL browser, http:// eqtl.uchicago.edu/). 51 In summary, out of the seven distinct highquality, statistically significant eQTLs discovered in our study, four have been previously described as eQTLs, and three in prostate normal and tumor tissue specifically. Out of the gene targets for the three eQTLs that had not been described previously, FAM83F has no known protein function; FOXP4 is a transcription factor involved in development; and CYBRD1 is a reductase enzyme involved in iron metabolism in the duodenum.…”

Immune‐Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

“…Multiple SNPs within the chromosome 3 p21.31 region had evidence for eQTLs for the expression of CCR5 in monocytes 26. There was 1 missense SNP in the chromosome 3 p21.31 region (rs6441977) that was predicted to be “benign” by PolyPhen‐2 27; however, a frameshift mutation (rs333) is a known variant that results in a 32‐bp deletion and a nonfunctional receptor.…”

751 Identification of a Common Variant With Potential Pleiotropic Effect on Risk of Inflammatory Bowel Disease and Colorectal Cancer

“…In addition to CXCR2, expression quantitative trait loci studies have linked rs11676348 to expression of MR1 gene (40). MR1 encodes an antigen-presenting molecule specialized in presenting microbial vitamin B6 metabolites (41,42).…”