Abstract O.17: Whole Genome Sequencing of a six-member African American family with two Kawasaki disease-affected siblings identifies novel susceptibility variants
We performed Whole Genome Sequencing (WGS) of a 6-member African American (AA) family with 2 of the 4 children affected with KD. We identified 6,712,158 unique variants across all 6 individuals. We first analyzed the quartet of mother/father/affected sibs and then compared variants in the 2 affected vs. 2 unaffected sibs. Assuming a recessive inheritance model, we identified 49,591 transmitted candidate homozygous variants exclusively present in both affected sibs compared to their parents. The affected vs. unaffected sibling analysis generated 64,187 candidate homozygous variants exclusive to the affected sibs. The intersection of the two analyses identified 20,943 variants of which 303 - in 117 genes - were predicted to be deleterious. We validated the findings in a cohort of 405 KD subjects and 6,252 normal controls using 4,060,864 imputed genotypes. Association analysis of the imputed GWAS dataset for KD susceptibility using the allelic and recessive tests in PLINK found 438,343 SNPs (nominal P-value < 0.05). Of these, 17 variants in 10 genes were also among the 303 variants from the family analysis. These genes were ANGPT1, AS3MT, C10orf32, CMIP, CNNM2, LRIG2, MMP1, NT5C2, SLK, and TLR6. Of these, ANGPT1, MMP1, and TLR6 have been previously associated with KD. For SLK (serine-threonine protein kinase 2) rs10786779 located in the promoter, the homozygous A allele (risk) genotype showed significantly higher expression (p=0.04) in a cohort of 141 acute vs. convalescent mixed ethnic KD subjects on the Illumina HumanRef-12 V4 BeadChip.
Conclusion: This is the first analysis of WGS in KD and the first to focus on genetic susceptibility in AA children who are second only to Asian children in susceptibility to KD. This exploratory analysis provides new validated variants that may likely contribute to KD susceptibility in AA children.
Author Disclosures: J. Kim: None. C. Shimizu: None. H. Yang: None. O. Harismendy: None. L. Truong Hoang: None. E. Levy: None. R. Cimaz: None. D. Burgner: None. R.S.M. Yeung: None. C.C. Khor: None. S. Davila: None. M. Levin: None. T.W. Kuijpers: None. M.L. Hibberd: None. L. Ohno-Machado: None. J.C. Burns: None.
- © 2015 by American Heart Association, Inc.