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Association of Functional Polymorphisms in Interferon Regulatory Factor 2 (IRF2) with Susceptibility to Systemic Lupus Erythematosus: A Case-Control Association Study
- Source :
- PLoS ONE, PLoS ONE, Vol 9, Iss 10, p e109764 (2014)
- Publication Year :
- 2014
- Publisher :
- Public Library of Science, 2014.
-
Abstract
- Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of IRF2 in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether IRF2 polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 IRF2 tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4×10(-4), Bonferroni-corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18-1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r2: 0.30-1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7×10(-4), Pc = 0.037, OR 1.53, 95%CI 1.19-1.96) and rs62339994 (dominant model, P = 9.0×10(-4), Pc = 0.043, OR 1.46, 95%CI 1.17-1.82). The haplotype carrying both of the risk alleles (rs66801661A-rs62339994A) was significantly increased in SLE (P = 9.9×10(-4)), while the haplotype constituted by both of the non-risk alleles (rs66801661G-rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the IRF2 haplotypes on the transcriptional activity, and association of the IRF2 risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNγ stimulation (Tukey's test, P = 1.2×10(-4)). In conclusion, our observations supported the association of IRF2 with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2.
- Subjects :
- Adult
Male
Transcriptional Activation
Linkage disequilibrium
Interferon Regulatory Factor 2
Immunology
lcsh:Medicine
Single-nucleotide polymorphism
Autoimmunity
Biology
Systemic Lupus Erythematosus
Polymorphism, Single Nucleotide
Autoimmune Diseases
Rheumatology
Genetics
Genetics of the Immune System
Medicine and Health Sciences
Humans
Lupus Erythematosus, Systemic
Genetic Predisposition to Disease
Allele
lcsh:Science
Genetic Association Studies
Genetic association
Multidisciplinary
Lupus Erythematosus
Haplotype
lcsh:R
Biology and Life Sciences
Human Genetics
Odds ratio
Middle Aged
Haplotypes
Case-Control Studies
lcsh:Q
Clinical Immunology
Female
IRF2
Sequence Analysis
Interferon Regulatory Factor-2
Research Article
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....1029c1400a4eabd01428803859c87c8d