Gene–Gene and Gene-Sex Epistatic Interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in Systemic Lupus Erythematosus

Abstract

Several confirmed genetic susceptibility loci involved in the interferon signaling and Th17/B cell response for SLE in Chinese Han populations have been described. Available data also indicate that sex-specific genetic differences contribute to SLE susceptibility. The aim of this study was to test for gene–gene/gene-sex epistasis (interactions) in these known lupus susceptibility loci. Six single-nucleotide polymorphisms (SNPs) in MiR146a, IRF5, IKZF1, ETS1 and IL21 were genotyped by Sequenom MassArray system. A total of 1,825 subjects (858 SLE patients and 967 controls) were included in the final analysis. Epistasis was tested by additive model, multiplicative model and multifactor dimensionality reduction (MDR) method. Additive interaction analysis revealed interactions between IRF5 and IKZF1 (OR 2.26, 95% CI 1.48–3.44 [P = 1.21×104]). A similar tendency was also observed between IL21 and ETS1 by parametric methods. In addition, multiple high dimensional gene-gene or gene-sex interactions (three-and four-way) were identified by MDR analysis. Our study identified novel gene–gene/gene-sex interactions in lupus. Furthermore, these findings highlight sex, interferon pathway, and Th17/B cells as important contributors to the pathogenesis of SLE.

Genetic association and interaction between the IRF5 and TYK2 genes and systemic lupus erythematosus in the Han Chinese population

“…Recent studies showed that the rs10488631 of IRF5 was significantly associated with SLE in an Egypt population [32]. And the allele distribution and gene-gene interactions of IRF5(rs4728142) MiR146a, IKZF1, ETS1 and IL21 have been identified in a Chinese Han population [33]. Thus, it is necessary to detect a larger number of SNPs of IRF5 with the correlation to SLE in a further study.…”

MicroRNAs in the key events of systemic lupus erythematosus pathogenesis

“…although genome-wide association studies (GWas) reliably determine sle risk locations, some genetic predisposing factors may differ between populations. The complex genetic background of sle pathogenesis resides in variation of gene expression or in functional variants of members of multiple signalling pathways, immunologically active molecules or both 65 . some association studies focused on particular sNps of mirs genes and autoimmune diseases have already been performed, but failed to find any association with sle.…”

“…47 ). on the other hand, leng et al performed a gene-gene interaction analysis of mir-146a (rs57095329) and il-21 (rs907715 and rs2221903), irF-5, iKZF-1 and ets-1 (rs6590330), using direct counting and a chi-square test with a 2×2 factorial design, and found no interaction of mir-146a, in particular with ets-1 65 . The ets-1 rs6590330 sNp is in high linkage disequilibrium with the rs1128334 sNp (r 2 = 0.97) (ref.…”

Association between IL-21 polymorphism and systemic lupus erythematosus: a meta-analysis

“…Several polymorphisms in the IL-21 gene have been identified and several studies have been carried out to identify whether IL-21 polymorphisms were associated with SLE susceptibility (Sawalha et al, 2008;Hughes et al, 2011;Leng et al, 2012;Ding et al, 2012;Lan et al, 2014). Most of the studies focused on IL-21 rs907715 and rs2221903 polymorphisms.…”

“…Although possible associations of the IL-21 polymorphisms with SLE were reported, and many case-control studies were further performed to identify the association between IL-21 rs907715 and rs2221903 polymorphisms and SLE (Sawalha et al, 2008;Hughes et al, 2011;Leng et al, 2012;Ding et al, 2012;Lan et al, 2014). However, results from these studies were inconsistent, which may be due to the limitations in sample size and differences in ethnic populations.…”