Parks Christine G, Pandey Janardan P, Dooley Mary Anne, Treadwell Edward L, St Clair E W, Gilkeson Gary S, Feghali-Bostwick Carol A, Cooper Glinda S
National Institute of Environmental Health Sciences, Durham, NC, USA.
Hum Immunol. 2004 Jun;65(6):622-31. doi: 10.1016/j.humimm.2004.03.001.
Tumor necrosis factor (TNF) is involved in the pathogenesis of systemic lupus erythematosus (SLE), but the role of TNF polymorphisms in SLE susceptibility remains unclear. Previous studies in different populations report an inconsistent association of the TNF-alpha -308A allele with SLE, sometimes depending on the presence of HLA-DR3. We examined the association of polymorphisms in TNF-alpha (-308G/A, -238G/A) and TNFbeta (+252A/G) in a population-based study of SLE in the southeastern United States and considered TNF-SLE associations with respect to HLA-DR3 and DR2 and the interleukin (IL)-1alpha -889C/T polymorphism, previously linked to SLE in this population. Genotypes were analyzed for 230 recently diagnosed SLE patients who met American College of Rheumatology classification criteria and 276 age- and sex-matched controls, randomly selected from driver's license registries. Carriage of the TNF-alpha -308A allele was significantly associated with SLE in Caucasians (OR = 2.3; 95% CI 1.4, 3.9), but not African Americans. Analyses stratified by IL-1alpha -889 genotypes (C/C vs C/T or T/T) revealed independent associations of SLE with TNF-alpha -308A or HLA-DR2 and DR3. This reflected a significant interaction of TNF and IL-1 genotypes in Caucasians, and yielded a strong association (OR = 8.0, p < 0.00001) for the combined "HLA-DR3, TNF-alpha -308A, IL-1alpha -889C/C" genotype. These findings provide evidence of cytokine gene epistasis in SLE susceptibility.
肿瘤坏死因子（TNF）参与系统性红斑狼疮（SLE）的发病机制，但TNF基因多态性在SLE易感性中的作用仍不清楚。以往在不同人群中的研究报告了TNF-α -308A等位基因与SLE的关联不一致，有时取决于HLA-DR3的存在。我们在美国东南部一项基于人群的SLE研究中，检测了TNF-α（-308G/A、-238G/A）和TNF-β（+252A/G）基因多态性的关联，并考虑了TNF与SLE的关联以及HLA-DR3和DR2以及白细胞介素（IL）-1α -889C/T多态性，该多态性此前已与该人群中的SLE相关联。对230例符合美国风湿病学会分类标准的新诊断SLE患者和276例年龄和性别匹配的对照进行了基因分型，这些对照是从驾照登记处随机选取的。TNF-α -308A等位基因的携带在白种人中与SLE显著相关（OR = 2.3；95%CI 1.4，3.9），但在非裔美国人中并非如此。按IL-1α -889基因型（C/C与C/T或T/T）分层分析显示，SLE与TNF-α -308A或HLA-DR2和DR3存在独立关联。这反映了白种人中TNF和IL-1基因型之间的显著相互作用，并且对于组合的“HLA-DR3、TNF-α -308A、IL-1α -889C/C”基因型产生了强烈关联（OR = 8.0，p < 0.00001）。这些发现为SLE易感性中的细胞因子基因上位效应提供了证据。
