Genome-Wide Association Study Identifies Novel Susceptibility Genes Associated with Coronary Artery Aneurysm Formation in Kawasaki Disease

• Published in: PloS one Vol. 11; no. 5; p. e0154943
• Main Authors: Kuo, Ho-Chang, Li, Sung-Chou, Guo, Mindy Ming-Huey, Huang, Ying-Hsien, Yu, Hong-Ren, Huang, Fu-Chen, Jiao, Fuyong, Kuo, Hsing-Chun, Andrade, Jorge, Chan, Wen-Ching
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12-05-2016; Public Library of Science (PLoS)
• Subjects: Aneurysm; Aneurysms; Arteries; Biology and Life Sciences; Blood vessels; Cardiac muscle; Cardiovascular disease; Child; Children; Coding; Coronary Aneurysm - complications; Coronary Aneurysm - genetics; Coronary arteries; Coronary artery; Coronary vessels; Coronary Vessels - pathology; Development and progression; DNA methylation; Drug dosages; Gene expression; Gene Ontology; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotyping; Health risk assessment; Heart diseases; Heredity; Hospitals; Humans; Immunoglobulins; Informatics; Intravenous administration; Kawasaki disease; Kawasaki syndrome; Knowledge representation; Laboratories; Lesions; Linkage Disequilibrium - genetics; Matrix Metalloproteinase 9 - genetics; Medical research; Medicine; Medicine and Health Sciences; Models, Genetic; Mucocutaneous lymph node syndrome; Mucocutaneous Lymph Node Syndrome - complications; Mucocutaneous Lymph Node Syndrome - genetics; Muscles; Mutation; Pathogenesis; Patients; Pediatrics; Phosphorylation; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Precision medicine; Proteomics; Risk Factors; Threonine; Tubulin; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-TNF; Vasculitis; Chicago Illinois; United States > US; Illinois; China; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154943

Kawasaki disease (KD) or Kawasaki syndrome is known as a vasculitis of small to medium-sized vessels, and coronary arteries are predominantly involved in childhood. Generally, 20-25% of untreated with IVIG and 3-5% of treated KD patients have been developed coronary artery lesions (CALs), such as dilatation and aneurysm. Understanding how coronary artery aneurysms (CAAs) are established and maintained in KD patients is therefore of great importance. Upon our previous genotyping data of 157 valid KD subjects, a genome-wide association study (GWAS) has been conducted among 11 (7%) CAA-developed KD patients to reveal five significant genetic variants passed pre-defined thresholds and resulted in two novel susceptibility protein-coding genes, which are NEBL (rs16921209 (P = 7.44 × 10(-9); OR = 32.22) and rs7922552 (P = 8.43 × 10(-9); OR = 32.0)) and TUBA3C (rs17076896 (P = 8.04 × 10(-9); OR = 21.03)). Their known functions have been reported to associate with cardiac muscle and tubulin, respectively. As a result, this might imply their putative roles of establishing CAAs during KD progression. Additionally, various model analyses have been utilized to determine dominant and recessive inheritance patterns of identified susceptibility mutations. Finally, all susceptibility genes hit by significant genetic variants were further investigated and the top three representative gene-ontology (GO) clusters were regulation of cell projection organization, neuron recognition, and peptidyl-threonine phosphorylation. Our results help to depict the potential routes of the pathogenesis of CAAs in KD patients and will facilitate researchers to improve the diagnosis and prognosis of KD in personalized medicine.