The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

Abstract

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

Genetics of systemic lupus erythematosus and Sjögren's syndrome: an update

“…Most interesting has been the targeted next-generation sequencing of the MHC region, where a haplotype with regulatory polymorphisms was associated with changes in gene expression of the HLA class II molecules [15 && ]. Among non-HLA genes, the IRF5-TNPO3 region shows the strongest and most consistent association signals with odds ratios (ORs) of 2.0 [12,[16][17][18][19][20][21] in all populations studied. In fact, a recent GWAS in Hispanics with enriched Native American ancestry revealed IRF5 as the major locus in SLE, whereas the HLA association was secondary [22 && ].…”

IRF5 Deficiency Ameliorates Lupus but Promotes Atherosclerosis and Metabolic Dysfunction in a Mouse Model of Lupus-Associated Atherosclerosis

“…Gain-of-function polymorphisms in the transcription factor interferon regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing a number of autoimmune diseases including SLE, scleroderma, Sjögren’s disease, rheumatoid arthritis and inflammatory bowel disease (14, 15). IRF5 was originally identified as a transcription factor involved in the induction of type I interferons and pro-inflammatory cytokines by viral infection (16, 17) and subsequently was shown to play an important role in pro-inflammatory cytokine production following Toll-like receptor (TLR) signaling (18, 19).…”

CressInt : A user-friendly web resource for genome-scale exploration of gene regulation in Arabidopsis thaliana

“…[8], and a similar procedure used in that study and another recent study [14] to identify TFs whose binding might be affected by the alleles of 4,355,790 naturally occurring A. thaliana genetic variants [6]. One type of data produced by a PBM experiment is the E-score, which ranges from −0.50 to +0.50, and quantifies the relative preference of the binding of the tested TF to each of the 32,896 possible 8 base sequences [11].…”