Combination of TNF-RII, CYP1A1 and GSTM1 polymorphisms and the risk of Japanese SLE: Findings from the KYSS study

Objectives: Association of the polymorphisms of the genes, TNF receptor type II gene (TNF-RII), cytochrome P4501A1 gene (CYP1A1) and glutathione S-transferase M1 gene (GSTM1), with SLE was investigated. TNF-RII mediates inflammatory and immune response, whereas CYP1A1 and GSTM1 are involved in the metabolism of xenobiotics. These three genes are involved in the generation of reactive oxygen species (ROS), which play a critical role for autoimmune diseases. Methods: A total of 152 SLE patients and 427 healthy individuals in a female Japanese population were enrolled in the study. Case-control studies were performed for the polymorphisms of these three genes. Results. The carriers of TNF-RII 196R were at a significantly increased risk for SLE with odds ratio (OR) of 1.59 (95% CI=1.01, 2.52). CYP1A1 3801C homozygotes had a significantly increased risk of SLE (OR=2.47, 95% CI=1.28, 4.78). On the other hand, GSTM1 null genotype was not associated with SLE risk. As for combination action of two loci, CYP1A1 3801C/GSTM1 null combination was more strongly associated with an increased risk of SLE (OR=4.35; 95% CI=1.76, 10.73). Moreover, TNF-RII 196M/CYP1A1 3801C/GSTM1 null genotype combination was most significantly associated with SLE (OR=5.83; 95% CI=2, 17.04). Conclusions: The individuals carrying two or more 'at-risk' genotypes of TNF-RII, CYP1A1 and GSTM1 had a significantly more increased risk for SLE compared with those having each 'at-risk' genotype. Combination of the risk genotypes will be important to more clearly identify the population at risk for SLE.