Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease.


Khor, CC; Davila, S; Shimizu, C; Sheng, S; Matsubara, T; Suzuki, Y; Newburger, JW; Baker, A; Burgner, D; Breunis, W; Kuijpers, T; Wright, VJ; Levin, M; Hibberd, ML; Burns, JC; US and International Kawasaki Disease Genetics Consortia, ; (2011) Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease. Journal of medical genetics, 48 (7). pp. 467-72. ISSN 0022-2593 DOI: https://doi.org/10.1136/jmg.2010.086611

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Abstract

BACKGROUND: Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000 individuals to identify new genetic contributions to KD susceptibility. METHODS AND RESULTS: A 26-family linkage study followed by fine mapping was performed in a cohort of 1284 KD subjects and their family members (total 3248 individuals). Suggestive evidence of disease linkage (logarithm of odds (LOD) ?3.0, p<1.00×10(-4)) was found for five genomic locations (Chr 3q, 4q, 10p, 13q, 21q). Two of these loci (Chr 4q and Chr 13q) overlapped with validated findings from a recent KD genome-wide association study. Fine mapping analysis revealed three single nucleotide polymorphisms (SNPs) in ATP-binding cassette, subfamily C, member 4 (ABCC4) underlying the Chr 13q linkage peak showing evidence of association to KD (lowest p=8.82×10(-5); combined OR 2.00, 95% CI 1.41 to 2.83). ABCC4 is a multifunctional cyclic nucleotide transporter that stimulates the migratory capacity of dendritic cells. It is also a mediator of prostaglandin efflux from human cells and is inhibited by non-steroidal anti-inflammatory medications such as aspirin. CONCLUSION: These genetic data suggest that ABCC4 could play a fundamental role in KD pathogenesis with effects on immune activation and vascular response to injury.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
PubMed ID: 21571869
Web of Science ID: 291926800007
URI: http://researchonline.lshtm.ac.uk/id/eprint/292302

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