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 = 1.21×104]). 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.
References
[1]
Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, et al. (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41: 1234–1237.
[2]
Fu Q, Zhao J, Qian X, Wong JL, Kaufman KM, et al. (2011) Association of a functional IRF7 variant with systemic lupus erythematosus. Arthritis Rheum 63: 749–754.
[3]
Luo X, Yang W, Ye DQ, Cui H, Zhang Y, et al. (2011) A functional variant in microRNA-146a promoter modulates its expression and confers disease risk for systemic lupus erythematosus. PLoS Genet 7: e1002128.
[4]
Sawalha AH, Kaufman KM, Kelly JA, Adler AJ, Aberle T, et al. (2008) Genetic association of interleukin-21 polymorphisms with systemic lupus erythematosus. Ann Rheum Dis 67: 458–461.
[5]
Hughes T, Kim-Howard X, Kelly JA, Kaufman KM, Langefeld CD, et al. (2011) Fine-mapping and transethnic genotyping establish IL2/IL21 genetic association with lupus and localize this genetic effect to IL21. Arthritis Rheum 63: 1689–1697.
[6]
Ding L, Wang S, Chen GM, Leng RX, Pan HF, et al.. (2012) A Single Nucleotide Polymorphism of IL-21 Gene is associated with systemic lupus erythematosus in a Chinese population. Inflammation Doi: 10.1007/s10753-012-9497-7.
[7]
Hughes T, Adler A, Merrill JT, Kelly JA, Kaufman KM, et al. (2012) Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Ann Rheum Dis 71: 694–699.
[8]
Han S, Guthridge JM, Harley IT, Sestak AL, Kim-Howard X, et al. (2008) Osteopontin and systemic lupus erythematosus association: a probable gene-gender interaction. PLoS One 3: e0001757.
[9]
Shen N, Fu Q, Deng Y, Qian X, Zhao J, et al. (2010) Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A 107: 15838–15843.
[10]
Kariuki SN, Crow MK, Niewold TB (2008) The PTPN22 C1858T polymorphism is associated with skewing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor alpha levels in patients with lupus. Arthritis Rheum 58: 2818–2823.
[11]
Zhou XJ, Lu XL, Nath SK, Lv JC, Zhu SN, et al. (2012) Gene-gene interaction of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in systemic lupus erythematosus. Arthritis Rheum 64: 222–231.
[12]
Hughes T, Adler A, Kelly JA, Kaufman KM, Williams AH, et al. (2012) Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arthritis Rheum 64: 485–492.
[13]
Su MW, Tung KY, Liang PH, Tsai CH, Kuo NW, et al. (2012) Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach. PLoS One 7: e30694.
[14]
Hu SJ, Wen LL, Hu X, Yin XY, Cui Y, et al.. (2012) IKZF1: a critical role in the pathogenesis of systemic lupus erythematosus? Mod Rheumatol Doi: 10.1007/s10165-012-0706-x.
[15]
Fang CM, Roy S, Nielsen E, Paul M, Maul R, et al. (2012) Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response. Genes Immun 13: 421–430.
[16]
Dolff S, Abdulahad WH, Westra J, Doornbos-van der Meer B, Limburg PC, et al. (2011) Increase in IL-21 producing T-cells in patients with systemic lupus erythematosus. Arthritis Res Ther 13: R157.
[17]
Ettinger R, Kuchen S, Lipsky PE (2008) Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis 67 Suppl 3iii83–6.
[18]
Leng RX, Pan HF, Chen GM, Feng CC, Fan YG, et al. (2011) The dual nature of Ets-1: focus to the pathogenesis of systemic lupus erythematosus. Autoimmun Rev 10: 439–443.
[19]
Eyquem S, Chemin K, Fasseu M, Chopin M, Sigaux F, et al. (2004) The development of early and mature B cells is impaired in mice deficient for the Ets-1 transcription factor. Eur J Immunol 34: 3187–3196.
[20]
Wang D, John SA, Clements JL, Percy DH, Barton KP, et al. (2005) Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol 17: 1179–1191.
[21]
Moisan J, Grenningloh R, Bettelli E, Oukka M, Ho IC (2007) Ets-1 is a negative regulator of Th17 differentiation. J Exp Med 204: 2825–2835.
[22]
Yang W, Shen N, Ye DQ, Liu Q, Zhang Y, et al. (2010) Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet 6: e1000841.
[23]
Hahn LW, Ritchie MD, Moore JH (2003) Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 19: 376–382.
[24]
Ritchie MD, Hahn LW, Moore JH (2003) Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 24: 150–157.
[25]
Motsinger AA, Ritchie MD (2006) Multifactor dimensionality reduction: an analysis strategy for modelling and detecting gene-gene interactions in human genetics and pharmacogenomics studies. Hum Genomics 2: 318–328.
[26]
Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, et al. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25: 1271–1277.
[27]
Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40: 1725.
[28]
Kawasaki A, Ito S, Furukawa H, Hayashi T, Goto D, et al. (2010) Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study. Arthritis Res Ther 12: R174.
