104 - GENETIC SUSCEPTIBILITY OF KAWASAKI DISEASE IN HISPANIC TRIOS

BACKGROUND

The complex genetics of KD susceptibility have not been previously studied using whole genome sequencing (WGS) in a large cohort. In addition, children of Hispanic origin have been systematically excluded from previous genetic studies of KD.

METHODS

We performed whole genome sequencing on blood samples from 235 complete trios (proband, biologic mother and father) in our Hispanic KD cohort from San Diego. Raw FASTQ sequencing files were analyzed using the Illumina Dynamic Read Analysis for GENomics (DRAGEN) analysis pipeline, which consisted of read mapping/alignment, position sorting, duplicate marking, and variant calling. We performed the Transmission Equilibrium Test (TDT) for the region of interest on Chr 19 published by Onouchi and our group in 2008. We also performed family-informed gene burden testing on 20 trios with coronary artery aneurysm (CAA).

RESULTS

We successfully validated the findings of Onouchi near ITPKC gene in our Hispanic trios. Of the eight genic variants discovered in the Japanese cohort (case-control using genotyping data), the first four were validated in our Hispanic trios in alignment with results from the US mixed trios in the original study (Table 1). Further, in the same region of Chr 19q13.2, we identified the top novel variants in association with disease susceptibility, rs10402698 (chr19:40585951,  p-value 6.17e-07, REF:G, ALT:T) and rs7251057 (chr19:40585550,  p-value=1.379e-06, REF:T, ALT:C) in the SHKBP1 gene. SHKBP1 was not previously analyzed in the Japanese study. The gene burden testing validated SHKBP1 (P-value=1.83e-04), and also identified FCGBP as significantly enriched (P-value=2.41e-07) in the subgroup of trios whose KD probands had CAA. Using a microarray database, we determined that the two SHKBP1 variants are expression quantitative trait loci (eQTL) for LTBP4 that regulates TGFb1 signaling. Analysis of whole blood RNAseq from our Hispanic cohort is in progress to determine the effect of these variants in SHKBP1 on transcript abundance for LTBP4. The TGFb pathway plays an important role in endothelial cell homeostasis.

CONCLUSION

Our preliminary results from a targeted region in Chr 19 demonstrate the power of WGS analysis to reveal genetic drivers of KD pathogenesis. Future WGS analysis will include both trios and case:control analysis of tandem repeats, insertions, deletions, and inversions in addition to single nucleotide variants.