Comprehensive exploration of the effects of miRNA SNPs on monocyte gene expression

Abstract

We aimed to assess whether pri-miRNA SNPs (miSNPs) could influence monocyte gene expression, either through marginal association or by interacting with polymorphisms located in 3'UTR regions (3utrSNPs). We then conducted a genome-wide search for marginal miSNPs effects and pairwise miSNPs × 3utrSNPs interactions in a sample of 1,467 individuals for which genome-wide monocyte expression and genotype data were available. Statistical associations that survived multiple testing correction were tested for replication in an independent sample of 758 individuals with both monocyte gene expression and genotype data. In both studies, the hsa-mir-1279 rs1463335 was found to modulate in cis the expression of LYZ and in trans the expression of CNTN6, CTRC, COPZ2, KRT9, LRRFIP1, NOD1, PCDHA6, ST5 and TRAF3IP2 genes, supporting the role of hsa-mir-1279 as a regulator of several genes in monocytes. In addition, we identified two robust miSNPs × 3utrSNPs interactions, one involving HLA-DPB1 rs1042448 and hsa-mir-219-1 rs107822, the second the H1F0 rs1894644 and hsa-mir-659 rs5750504, modulating the expression of the associated genes.As some of the aforementioned genes have previously been reported to reside at disease-associated loci, our findings provide novel arguments supporting the hypothesis that the genetic variability of miRNAs could also contribute to the susceptibility to human diseases.

Figure 1. HLA-DPB1 rs1042448 × hsa-mir-219-1 rs107822 interaction on HLA-DPB1 monocyte expression.

In the Gutenberg Health Study, the rs1042248/rs107822 pair was tagged by rs3128923/rs213208. In the Cardiogenics Transcriptomic Study, the corresponding tagging pair was rs3117222/rs439205.

Figure 2. H1F0 rs1894644 × hsa-mir-659 rs5750504 interaction on H1F0 monocyte expression.

In the Gutenberg Health Study, the rs1894644/rs5750504 pair was tagged by rs763137/rs2899293. In the Cardiogenics Transcriptomic Study, the corresponding tagging pair was rs1894644/rs6000905.

Figure 3. Location of genes, miSNP and 3'UTR SNPs at the two detected interacting loci.

Gene are indicated as black rectangles with grey 3'UTR. Bold red and blue SNPs represent miSNPs and 3utrSNPs respectively. Corresponding proxies are non-bold coloured. Top: HLA-DBP1 locus on chromosome 6; Bottom: H1F0 locus on chromosome 22.