Inflammatory gene polymorphisms and susceptibility to Kawasaki disease and its arterial sequelae

OBJECTIVE. We tested the hypothesis that single-nucleotide polymorphisms of inflammatory genes C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-alpha) may exert influence on susceptibility to Kawasaki disease and its arterial sequelae. METHODS. We analyzed the CRP + 1444 C -> T and TNF-alpha - 308 G -> A polymorphisms in 167 patients aged 8.9 +/- 4.1 years with a history of Kawasaki disease (73 with and 94 without coronary aneurysms) and 124 healthy control subjects. For patients with Kawasaki disease, we further determined whether these single-nucleotide polymorphisms were associated with coronary aneurysms, carotid arterial stiffening, and intima-media thickness. RESULTS. Genotypic and allelic frequencies of CRP + 1444 for T carrier and TNF-alpha - 308 for A carrier were significantly higher in patients than in control subjects. The genotypic and allelic distributions did not differ between patients with and those without coronary aneurysms; however, patients with CRP + 1444 CT/TT genotype compared with those with a CC genotype and patients with TNF-alpha - 308 GA/AA genotype compared with those with a GG genotype had significantly greater carotid arterial stiffness and intima-media thickness. Carriers of both CRP + 1444 T allele and TNF-alpha - 308 A allele had the highest susceptibility to Kawasaki disease and a significant trend of increased arterial stiffness and intima-media thickness compared with those who carried either 1 or none of the rare alleles. Multiple linear regression analysis identified CRP + 1444 allele carrier as a significant determinant of both carotid stiffness and carotid intima-media thickness and TNF-alpha - 308 A allele carrier as a determinant of only intima-media thickness. CONCLUSIONS. Our findings suggest that CRP + 1444 C -> T and TNF-alpha - 308 G -> A polymorphisms are associated with predisposition to Kawasaki disease and, in patients with Kawasaki disease, increased carotid arterial stiffness and intima-media thickness in the long-term.