The influence of polymorphisms in DC-SIGN with kawasaki disease (KD) susceptibility and treatment outcomes in hispanics

Abstract

Functional polymorphisms of the C-type lectin CD209 (DC-SIGN) affect susceptibility to infection by viruses including HIV by modulating immune response. DC-SIGN has also been identified as a specific receptor for sialylated Fc, the component responsible for the anti-inflammatory action of intravenous immunoglobulin (IVIG), the principal therapy for Kawasaki Disease (KD). We hypothesized that these DC-SIGN polymorphisms modify immune response in KD and influence susceptibility, IVIG refractoriness (IVIG-R) - defined by AHA guidelines, and coronary artery disease (CAD) - dilation (Z-score>2.5) or aneurysm persisting>6 weeks after appropriate IVIG treatment (2 gm/kg). We genotyped 5 single nucleotide polymorphisms in the promoter region of DC-SIGN using Taqman assay in a cohort of 427 KD patients and their available biological parents (279 trios, 107 case-single parent pair, 41 patients only). A case-control approach was performed to examine the differential distribution of alleles and genotypes according to IVIG-R and CAD. KD susceptibility was performed by the transmission disequilibrium test (TDT) in FBAT. All analyses were performed separately for Caucasians, Asians, and Hispanics as determined by the principal component analysis (PCA) of 155 Ancestry Informative Markers (AIMs). Two SNPs (rs2287886 and rs4804804) showed significant genotype association with IVIG-R among Hispanics (49 responders and 19 non-responders (p-value<0.02) and rs2287886 and rs4804803 showed both allelic and genotype associations with CAD also in the Hispanic populations (31 CAD and 44 non-CAD, p-value<0.004). In the additive model of the TDT, rs4804803 (n=15 trios; z=2.36, p=0.02) and rs4804804 (n=33 trios; z=0.02, p=0.01) showed an excess of transmission of the A and G alleles, respectively from informative parents to affected Hispanic offspring. However, no associations were found in other ethnic groups with variants in DC-SIGN. Our data show DC-SIGN associations specific for a Hispanic population of primarily Mexican and Central American origin. These observations may explain the particularly severe KD cases including those with shock syndrome and coronary aneurysms reported in Hispanic populations in the Western U.S.