title: Gene-gene and gene-sex epistatic interactions of MiR146a, IRF5, IKZF1, ETS1 and IL21 in systemic lupus erythematosus.
abstract: 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.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People's Republic of China.
authors.forename: Rui-Xue
authors.initials: RX
authors.lastname: Leng
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Han
authors.initials: H
authors.lastname: Cen
authors.forename: Mo
authors.initials: M
authors.lastname: Zhou
authors.forename: Chen-Chen
authors.initials: CC
authors.lastname: Feng
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xiao-Ke
authors.initials: XK
authors.lastname: Yang
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhai
authors.forename: Bao-Zhu
authors.initials: BZ
authors.lastname: Li
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Gui-Mei
authors.initials: GM
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Pan
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Ye
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007378:Interleukins / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D012737:Sex Factors; D000098546:Interleukin-21
chemical_list: C494041:ETS1 protein, human; C497239:IKZF1 protein, human; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D007378:Interleukins; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D050784:Proto-Oncogene Protein c-ets-1; D051740:Ikaros Transcription Factor; D000098546:Interleukin-21