A regulatory polymorphism in promoter region of TNFR1 gene is associated with Kawasaki disease in Chinese individuals

Tumor necrosis factor (TNF) and the TNF receptor superfamily (TNF-TNFR) plays very important roles in the pathogenesis of Kawasaki disease (KD) by leukocyte recruitment, upregulation of matrix-degrading enzymes and proinflammatory cytokines. This study aims to investigate whether potential polymorphisms in TNF receptor superfamily member 1A gene (TNFR1) are associated with KD and its effects on transcriptions activity of TNFR1. Genetic variations of TNFR1 promoter and coding regions in 132 unrelated patients with KD and 212 age-matched healthy controls recruited from a population of Chinese individuals were screened by direct sequencing. Bioinformatics analysis and function assays were performed to investigate the association between genetic variations and KD, and its effects on transcription activity of TNFR1. Five polymorphisms, termed −609T/G, −581A/G, −421G/A, −383A/C, and +36A/G, were identified in the subjects, of which −421A/G was reported for the first time. In particular, bioinformatics analysis and function assay confirmed that −609T allele resulted in allele-specific strengthening of TNFR1 transcription and was significantly associated with KD (p = 2.951E-08, odds ratio = 2.42, 95% confidence interval = 1.76–3.13). Furthermore, the haplotype TAGAA showed a relatively higher frequency in patients with KD compared with healthy controls (p = 3.446E-07, odds ratio = 2.26, 95% confidence interval = 1.65–3.11). Therefore, our results suggested that regulatory polymorphism −609T/G and the haplotype TAGAA may be related to increased susceptibility to KD in Chinese individuals.