[The correlation between Kawasaki disease and polymorphisms of Tumor necrosis factor alpha and interleukin-10 gene promoter].

Objective: Kawasaki disease (KD) is an acute febrile vasculitic syndrome of unknown etiology that preferentially affects coronary artery. It has been suggested that proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) are key players during acute KD. Recently, the polymorphisms relative to major transcriptional start site of TNF-alpha and IL-10 gene were shown to influence the level of TNF-alpha and IL-10 production in vitro. This study was aimed to investigate the genetic association of TNF-alpha and IL-10 promoter polymorphisms in juvenile patients of Han nationality with KD, and to investigate the possible associations with clinical manifestations of the disease.

Methods: Four polymorphism sites of TNF-alpha and IL-10 gene promoter regions from 96 children with KD were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). One hundred and sixty age-matched normal children of the Han nationality were used as control. All patients accepted Doppler echocardiography examination in order to differentiate coronary artery lesions.

Results: There was significant difference in allele frequencies of -308 (A/G) site of the TNF-alpha gene between children of the Han nationality and those of Japanese and Caucasian in America. There were significant differences in the allele frequencies of -1082 (G/A), -819 (C/T) and -592 (A/C) of IL-10 gene between children of the Han nationality and their British Counterparts (P < 0.01). There was no significant difference in allele frequencies of -308 (A/G) site of TNF-alpha gene between children with KD and normal controls. There was no significant difference in the haplotypes and the allele frequencies of the above three sites of IL-10 between the two groups. However, when clinical features were examined, the genotype frequency of TNF-alpha-308A was significantly higher in IVIG-resistant KD patients than that of TNF-alpha-308G genotype (67% vs 5%, chi(c)(2) = 90.48, P < 0.01). The genotype of TNF-alpha-308A was closely associated with IVIG-resistant KD (P < 0.01, relative risk 42.25, 95% confidence interval 15.81-112.88). The haplotype frequency of IL-10 -1082A/-819T/-592A was also higher in patients with coronary artery lesion (CAL) caused by KD than those of Non-ATA haplotype (52% vs 20%, chi(2) = 18.36, P < 0.01). The haplotypes of IL-10 -1082A/-819T/-592A was significantly associated with CAL caused by KD (P < 0.01, relative risk 4.26, 95% confidence interval 2.20-8.25).

Conclusion: The genotype of TNF-alpha-308A is one of the important factors that probably influence the therapeutic effect of KD. The haplotypes (-1082/-819/-592) of IL-10 gene promoter might be related to the pathogenesis of coronary artery complication of KD and -1082A/-819T/-592A haplotypes might be regarded as a genetic marker of risk factor for coronary artery lesion in KD.