Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes

Abstract

This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar rash, as well as the presence of autoantibodies against nucleic acid-containing complexes. Genotyping was carried out in two Danish cohorts [Copenhagen (CPH) and Odense (ODE)] totaling 344 patients and was compared with 641 previously genotyped healthy controls. In the ODE cohort, the patients were only genotyped for the rs1990760 polymorphism of IFIH1. Single nucleotide polymorphisms (SNPs) were determined by a multiplex bead-based assay (CPH cohort) or real-time PCR (ODE cohort). Associations were investigated using the Cochran-Armitage trend test. The odds ratio (OR) for minor allele homozygotes versus major allele homozygotes suggested a protective effect of the IFIH1 rs1990760 SNP for SLE in the ODE cohort [OR 0.52, 95 % confidence intervals (95 % CI) 0.31-0.88, Pcorr. = 0.05] but not in the CPH cohort, although the OR suggested a trend in the same direction, and when combining the two patient cohorts, ORs were 0.57, 95 % CI 0.37-0.88. None of the other investigated polymorphisms showed any association with SLE. Regarding phenotypes, we found a statistically significant association between rs1990760 and malar rash in the CPH cohort, with ORs suggesting a protective effect (OR 0.28, 95 % CI 0.13-0.62 for heterozygotes and OR 0.11, 95 % CI 0.03-0.41 for homozygotes, Pcorr. = 0.0001). There were no significant associations between rs1990760 and presence of anti-dsDNA, anti-U1RNP, or anti-Smith antibodies. Our study supports previous findings of an association between the rs1990760 polymorphism of IFIH1 and SLE and indicates that this SNP may also be associated with malar rash in SLE patients although this finding needs confirmation.

Association of interferon-induced helicase C domain (IFIH1) gene polymorphisms with systemic lupus erythematosus and a relevant updated meta-analysis

“…The updated meta-analysis in our study showed association between rs1990760 and SLE, pointing towards a protective role for the C allele, thus reinforcing previous results by Gateva et al (2009) and Enevold et al (2014). Despite the overall divergent results obtained with rs1990760 in SLE (Figure 2), our meta-analysis indicates either a protective association for the C allele or no association at all.…”

“…Despite the overall divergent results obtained with rs1990760 in SLE (Figure 2), our meta-analysis indicates either a protective association for the C allele or no association at all. These differences might be explained by taking into account the heterogeneous genetic background of the populations included in this and other studies, as also proposed by Enevold et al (2014). Sensitivity analysis estimates indicate that a large number of studies are required to produce more robust meta-analysis results.…”

“…Studies on IFN-induced genes improve our understanding of the regulatory mechanisms involved in activity and development of SLE. IFIH1 acts as a cytoplasmic sensor for dsRNA, causing activation of NF-kB, IFN-regulatory factors 3 and 7, and increased IFN production (Enevold et al, 2014). Additionally, IFIH1 is expressed in different cells of the immune system, playing a significant role in autoimmune diseases (Cen et al, 2013b).…”

“…Eleven and 109 articles were retrieved, respectively. Finally, IFIH1 rs1990760 was assessed in nine different association studies from six peer-reviewed articles, including a genome-wide association study (GWAS) (SLEGEN et al, 2008;Gateva et al, 2009;Gono et al, 2010;Cunninghame Graham et al, 2011;Cen et al, 2013a;Enevold et al, 2014). All articles ranged from 2008 to 2015 (Figure 1).…”

A meta-analysis of public microarray data identifies gene regulatory pathways deregulated in peripheral blood mononuclear cells from individuals with Systemic Lupus Erythematosus compared to those without

“…While none of the original studies highlighted a change in this pathway for any of the naive patient samples, Smiljanovic et al (2012) report TLR2 to be up-regulated in their tumor necrosis factor (TNF)-α in vitro-treated lupus monocytes compared to controls [39]. Furthermore, polymorphisms in TLR3, TLR7 and TLR9 genes have been associated with lupus patients in some populations [60–62] and a number of in vivo and in vitro studies have strongly implicated a number of TLRs to play a role in the pathogenesis of lupus [58]. By combining the datasets from the individual microarray studies here, we have similarly identified TLR signaling as a key regulatory mechanism that is differentially regulated in the PBMCs from lupus patients when compared to unaffected controls; and have demonstrated consistent differential regulation of TLR3.…”