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

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 credibleset 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. © The Author 2014.

• Fecha de publicación: 2015
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/24223
• Acceso en línea: https://doi.org/10.1093/hmg/ddu455; https://repository.urosario.edu.co/handle/10336/24223
• Palabra clave: Transcription factor; Transcription factor zbtb3; Unclassified drug; Dna binding protein; Interferon regulatory factor; Karyopherin beta; Allele; Ancestry group; Article; Autoimmune disease; Bayes theorem; Controlled study; Disease assessment; Dna sequence; European; Gene; Gene expression; Gene locus; Gene mapping; Genetic association; Genetic variability; Genotype; Haplotype; Human; Irf5 gene; Major clinical study; Primary biliary cirrhosis; Priority journal; Promoter region; Sjoegren syndrome; Systemic lupus erythematosus; Systemic sclerosis; Tnpo3 gene; Autoimmune disease; Case control study; Cohort analysis; Genetics; Male; Single nucleotide polymorphism; Systemic lupus erythematosus; Autoimmune diseases; Bayes theorem; Beta karyopherins; Case-control studies; Cohort studies; Dna-binding proteins; Haplotypes; Humans; Interferon regulatory factors; Male; systemic; single nucleotide; human; human; human; genetic; Irf5 protein; Tnpo3 protein; Zbtb3 protein; Lupus erythematosus; Polymorphism; Promoter regions
• License: Abierto (Texto Completo)