| Backgroud Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmunedisease characterized by a diverse array of autoantibody production, complementactivation and immune complex deposition, causing tissue and organ damage. Theaetiology of SLE is incompletely understood, but genetic factors play an important rolein the susceptibility to the disease. Recent candidate gene and genome-wide associationstudies (GWAS) led to the discovery and validation of multiple susceptibility loci forSLE. However, the heritability of SLE cannot be completely explained by thesusceptibility loci already discovered. Now, numerous studies have suggested thatgene–gene interactions (Epistasis) that might account for some of the “missingheritability” in SLE.Objective To validate the association in previously identified Type I Interferon and (THelp17Cell) Th17cell signaling-related single-nucleotide polymorphisms (SNPs) andsearch among them for gene–gene interactions that might account for some of the“missing heritability” in SLE.Methods We conducted this study by a two stage design. In the first stage, the locipreviously reported for SLE in Chinese include genes involved in Type I interferonsignaling and Th17cell regulation, were investigetied. In the second stage, we willcomprehensively explore gene-gene interactions based on identified SNPs in Th17signaling pathway. SLE patients were recruited at the Department of Rheumatology ofAuhui Provincial Hospital and First Affiliated Hospital, Anhui Medical University.Diagnosis of SLE was established according to the1997revised criteria of American College Rheumatology (ACR). Healthy volunteers were included as normal controls.Susceptibility loci were genotyped by Sequenom MassArray system. Diseaseassociations were analyzed by chi-square tests or logistic regression analysis. A multiplelogistic regression model was used to estimate the multiplicative interactions, andadditive interactions were analyzed by2×2factorial designs.Results In the first stage (858SLE patients and967controls), we found that the IL21(rs907715) were associated with susceptibility to SLE in Chinese Han populations[OR=0.84,95%confidence interval (CI)=0.74-0.96, P=0.01]. After adjusting for ageand sex, we observed a significant multiplicative interaction effect between IL21(rs2221903) and ETS1(rs6590330)(β=0.26, P=0.02, codominant model), IL21(rs907715) and ETS1(rs6590330)(β=0.58, P=0.03, dominant model). The results ofmultiplicative interaction are synergistic (β>0). Significant additive interaction effectalso was identified between IL21(rs907715) and ETS1(rs6590330)[relative excess riskdue to interaction (RERI)=0.73,95%CI=0.33-1.13, P=3.29×10-4; attributable proportiondue to interaction (AP)=0.44,95%CI=0.14-0.74, P=4.62×10-3], ETS1(rs6590330) andIL21(rs2221903)[RERI=0.59,95%CI=-0.09-1.26), P=0.09; AP=0.30,95%CI=0.002-0.60, P=0.05]. In addition, we also found an additive interactiontendency between IRF5(rs4728142) and IKZF1(rs4917014). In the second stage, weconfirmed that IL21(rs6835457)(OR=0.88,95%CI=0.80-0.96, P=4.84×10-3), PPP2CA(rs7704116)(OR=1.60,95%CI=1.31-1.96, P=3.35×10-6) and IFNG (rs2069705)(OR=1.13,95%CI=1.01-1.26, P=0.04) were associated with susceptibility to SLE inChinese Han populations. After adjusting for age and sex, we further identified asignificant multiplicative interaction effect between IL21(rs6835457) and ETS1(rs6590330) in a larger sample set (1,481SLE patients and2,266controls)(β=0.41,P=0.02, dominant model). Additive interaction analysis revealed epistatic effectbetween IL21(rs6835457) and ETS1(rs6590330)(RERI=0.57,95%CI=0.26-0.87,P=2.71×10-4; AP=0.34,95%CI=0.13-0.55, P=1.63×10-3], TBX21(rs4794067) and IFNG (rs2069705)[RERI=-0.44,95%CI=-0.81-(-0.08), P=0.02; AP=-0.45,95%CI=-0.88-(-0.03), P=0.04].Conclusions In conclusion, our study confirmed that several SNPs involved in Type Iinterferon signaling and Th17cell regulation were significantly associated with SLErisk in a Chinese population. Moreover, we also identified novel gene–gene interactionsin SLE. All these findings suggest that genetic variations and gene–gene epistasis mayjointly affect the susceptibility of SLE. |
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