IRF7／KIAA154和STAT4基因多态性与中国汉族人群系统性红斑狼疮的相关性

Associations of IRF7/KIAA1542 and STAT4 polymorphisms with systemic lupus erythematosus in Chinese Han population

目的 分析IRF7/KIAA1542（rs4963128,rs2246614）和STAT4 （rs7574865）基因多态位点与中国汉族人群SLE易感性的关系,探讨这些基因多态性与SLE患者狼疮肾炎和自身抗体产生及各种临床症状的相关性.方法 采用MALDI-TOF-MS基因分型法对748例SLE患者（SLE组）和750名健康人（健康对照组）进行关联分析.同时采用IIF法检测抗dsDNA抗体,采用免疫双扩散法检测抗SSA抗体、抗SSB抗体、抗Sm抗体和抗RNP抗体,并分析这些抗体与SLE的关系.结果 在健康对照组中rs574865（STAT4）T/T、T/G、G/G基因型频率和T、G等位基因频率分别为9.4%、45.6%、45.0%、32.2%、67.8%,SLE组为17.0%、48.1%、34.9%,41.0%59.0%,两组基因型频率和等位基因频率比较,差异有统计学意义（x^2=26.30,P〈0.01）.另外,与健康对照组比较,SLE组中T/T基因型频率和T等位基因频率明显升高,而且在3个遗传模型（加性模型、显性模型、隐性模型）下基因型频率差异都有统计学意义（P均〈0.01）.rs4963128和rs2246614（IRF7/KIAA1542）2个多态位点的基因型频率和等位基因频率在SLE组和健康对照组中的差异均无统计学意义（x2值分别为4.49、5.32,P均〉0.05）,但rs2246614位点基因型频率在隐性遗传模型下的差异具有统计学意义（P〈0.05）,而rs4963128位点基因型频率在3个遗传模型下的差异均无统计学意义（P均〉0.05）.临床症状分析结果显示,rs4963128（IRF7/KIAA1542）在狼疮肾炎组（OR=2.69,95% CI=1.89～3.82,P〈0.01）、抗SSA抗体组（OR=0.61,95%C/=0.43～0.87,P〈0.05）和抗SSB抗体组（OR=0.36,95% CI=0.23～0.56,P〈0.01）的差异都有统计学意义.同时,rs2246614在关节症状阳性组与阴性组中的差异有统计学意义（OR=1.34,95% CI：1.06～1.69,P〈0.05）.结论 rs7574865（STAT4）与中国汉族人群SLE易感性相关.rs4963125,rs2246614（IRF7/KIAA1542）虽然与SLE易感性无明确相关性,但却与SLE患者的多种临床症状（如狼疮肾炎、关节症状）和抗SSA抗体、抗SSB抗体的产生有相关性.

Objective To investigate genetic polymorphisms of IRF7/KIAA1542 （rs4963128, rs2246614） and STAT4 （rs7574865） and their relationships with lupus nephritis and various autoantibodies present in Chinese Han population of SLE patients. Methods A total of 748 SLE patients and 750 healthy controls belonging to the Chinese population were enrolled into this study. They were genotyped using MALDI-TOF-MS method. Autoantibodies including anti-SSA, anti-SSB, anti-Sm, anti-RNP and anti-dsDNA were determined either by indirect immunofluorescence or double immunodiffusion methods. Results In the healthy group, rs7574865 （STAT4） T/T, T/G, G/G genotype frequency and T, G allele frequencies were as follows： 9.4% , 45. 6% , 45. 0% , 32. 2% , 67. 8% , the corresponding case group as follows： 17.0% , 48.1%, 34.9%, 41.0%, 59.0%, genotype and allele frequencies were significantly different （x2 = 26.30, P〈0.01）. Compared with the control group, in the case group, T/T genotype frequency and T allele frequency were significantly increased, and in three genetic models （ additive model, dominant model, recessive model）, the genotype frequencies were significant difference （P 〈0. 01）. Two polymorphic loci of rs4963128 and rs2246614 （IRF7/KIAA1542） were not statistically significant （x2 =4.49,5.32,P〉0.05） in case group and control group, but the rs2246614 genotype frequencies had a statistically significant in recessive model （P 〈0. 05） , whereas rs4963128 genotype frequencies was no significant difference in the three genetic model （P=0.068, 0.958, 0.067, respectively）. In the clinical subphenotype analysis, IRF7/KIAA1542 （rs4963128） in lupus nephritis group （OR = 2. 69, 95% CI = 1. 89-3. 82, P 〈 0.01） ,anti-SSA antibody group （ OR = 0. 61, 95% CI = 0. 43-0. 87, P 〈 0. 05 ） and anti-SSB antibody group （ OR =0. 36, 95% CI = 0. 23-0. 56, P 〈 0.01） of the analysis were statistically significant. At the same time, IRF7/KIAA1542 （rs2246614） in the joint comparison of positive and negative symptoms were also statistically significant （OR=1.34, 95% CI = 1. 06-1. 69, P 〈 0. 05）. Conclusions This findings provide strong evidence suggesting that STAT4 （ rs7574865 ） is the susceptible factor of SLE in Chinese Han population. However, there is not a significant relationships between IRF7/KIAA1542 （rs4963128, rs2246614） polymorphisms and the risk of SLE, but the associations of IRF7/KIAA1542 （rs4963128, rs2246614） with the a variety of clinical subphenotypes, such as lupus nephritis, joint symptoms and production of anti-SSA antibody and anti-SSB antibody implicates IRF7/KIAA1542 as a putative candidate gene of SLE.