Gene-gene and gene-sex epistatic interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in systemic lupus erythematosus

• Published in: PloS one 2012-12, Vol.7 (12), p.e51090-e51090
• Main Authors: Leng, Rui-Xue, Wang, Wei, Cen, Han, Zhou, Mo, Feng, Chen-Chen, Zhu, Yan, Yang, Xiao-Ke, Yang, Mei, Zhai, Yu, Li, Bao-Zhu, Wang, Xiao-Song, Li, Rui, Chen, Gui-Mei, Chen, Hong, Pan, Hai-Feng, Ye, Dong-Qing
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Arthritis; Asian Continental Ancestry Group - genetics; Autoimmune diseases; B cells; Biological response modifiers; Biology; Chronic conditions; Disease susceptibility; Epidemiology; Epistasis; Epistasis, Genetic; Ets-1 protein; Female; Genes; Genetic aspects; Genetic Loci; Genetic Predisposition to Disease; Genomes; Genomics; Helper cells; Humans; Ikaros Transcription Factor - genetics; Interferon; Interferon Regulatory Factors - genetics; Interleukin 21; Interleukins - genetics; Laboratories; Loci; Lupus; Lupus Erythematosus, Systemic - genetics; Lymphocytes B; Lymphocytes T; Male; Medicine; MicroRNAs - genetics; Pathogenesis; Polymorphism, Single Nucleotide; Population; Proto-Oncogene Protein c-ets-1 - genetics; Public health; Sex; Sex Factors; Signaling; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Systemic lupus erythematosus
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0051090

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 = 1.21×10(4)]). 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.