Abstract 2790: Angiotensin Converting Enzyme and β3-Integrin Influence Susceptibility to Kawasaki Disease
Background: Kawasaki disease (KD) is a systemic vasculitis of children that causes coronary artery aneurysms in 25% of untreated patients. Evidence for genetic determinants of KD susceptibility includes a higher incidence among Asians and recognition of KD pedigrees.
Objective: To identify polymorphisms implicated in KD susceptibility through a candidate gene approach in a family-based association study.
Design/Methods: We genotyped 419 trios (838 parents and 419 KD children, 63% Caucasian, 12% Hispanic, 10% Asian) for 152 polymorphisms in 76 genes associated with cardiovascular health and the immune response using PCR based methods (Roche Molecular Systems, Alameda, CA). To minimize type II errors due to population heterogeneity, we performed a stratification analysis based on genetic similarities to create a more homogeneous study population of 333 mostly Caucasian KD trios. Preferential transmission of alleles was analyzed using the transmission/disequilibrium test (TDT; UN-PHASED). A false discovery rate (FDR) adjustment was used to correct for multiple comparisons. Conditional logistic regression on cases and matched ‘pseudocontrols’ was used to estimate the relative risks conferred by specific genotypes.
Results: After excluding the 19 polymorphisms for which <5% of parents were heterozygous, TDT analysis resulted in 12 nominally significant associations (p<0.05). The strongest results were for angiotensin converting enzyme (ACE) A(-262)T (p=0.0039) and β3-integrin (ITGB3) leu33pro (p=0.0064). Conditional logistic regression analysis for the ACE genotype showed additive protection of the T allele: relative risk for T/A= 0.69 (CI: 0.51– 0.92) and T/T= 0.55 (CI: 0.34 – 0.88)(p=0.015). For ITGB3, a significant relative risk of 1.63 (CI: 1.12–2.37, p=0.0095) was found for the combined leu/pro and pro/pro genotypes. Having both ITGB3 33pro and ACE-262A (Chr. 17q21–23) conferred a significantly additive increased risk (p=0.0007, FDR adjusted p<0.05).
Conclusions: ITGB3 and ACE, or linked loci, influence KD susceptibility. These proteins are known to play important roles in pro-inflammatory signaling pathways, platelet activation, viral cell entry, and vascular wall remodeling, all of which could impact KD pathogenesis.