Whole genome sequencing of an African American family highlights toll like receptor 6 variants in Kawasaki disease susceptibility.
Kawasaki disease (KD) is the most common acquired pediatric heart disease. We analyzed Whole Genome Sequences (WGS) from a 6-member African American family in which KD affected two of four children. We sought rare, potentially causative genotypes by sequentially applying the following WGS filters: sequence quality scores, inheritance model (recessive homozygous and compound heterozygous), predicted deleteriousness, allele frequency, genes in KD-associated pathways or with significant associations in published KD genome-wide association studies (GWAS), and with differential expression in KD blood transcriptomes. Biologically plausible genotypes were identified in twelve variants in six genes in the two affected children. The affected siblings were compound heterozygous for the rare variants p.Leu194Pro and p.Arg247Lys in Toll-like receptor 6 (TLR6), which affect TLR6 signaling. The affected children were also homozygous for three common, linked (r2 = 1) intronic single nucleotide variants (SNVs) in TLR6 (rs56245262, rs56083757 and rs7669329), that have previously shown association with KD in cohorts of European descent. Using transcriptome data from pre-treatment whole blood of KD subjects (n = 146), expression quantitative trait loci (eQTL) analyses were performed. Subjects homozygous for the intronic risk allele (A allele of TLR6 rs56245262) had differential expression of Interleukin-6 (IL-6) as a function of genotype (p = 0.0007) and a higher erythrocyte sedimentation rate at diagnosis. TLR6 plays an important role in pathogen-associated molecular pattern recognition, and sequence variations may affect binding affinities that in turn influence KD susceptibility. This integrative genomic approach illustrates how the analysis of WGS in multiplex families with a complex genetic disease allows examination of both the common disease-common variant and common disease-rare variant hypotheses.
Department of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America.
Jihoon
J
Kim
Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
Chisato
C
Shimizu
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, California, United States of America.
Stephen F
http://orcid.org/0000-0002-3758-4631
SF
Kingsmore
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, California, United States of America.
Narayanan
N
Veeraraghavan
Department of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America.|Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, California, United States of America.
Eric
E
Levy
Department of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America.
Andre M
AM
Ribeiro Dos Santos
Department of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America.
Hai
H
Yang
Illumina, San Diego, California, United States of America.
Jay
http://orcid.org/0000-0001-7637-1084
J
Flatley
Genome Institute of Singapore, Singapore, Singapore.
Long Truong
http://orcid.org/0000-0002-6808-6758
LT
Hoang
Depatment of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Martin L
ML
Hibberd
Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.|Rady Children's Hospital San Diego, San Diego, California, United States of America.
Adriana H
AH
Tremoulet
Department of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America.|Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
Olivier
O
Harismendy
Department of Biomedical Informatics, University of California San Diego, La Jolla, California, United States of America.
Lucila
L
Ohno-Machado
Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.|Rady Children's Hospital San Diego, San Diego, California, United States of America.
Jane C
JC
Burns
D001741:Black or African American / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D064326:MEF2 Transcription Factors / Q000235:genetics; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051216:Toll-Like Receptor 6 / Q000235:genetics*
D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; C495368:TLR6 protein, human; D051216:Toll-Like Receptor 6