Editors' ChoiceKawasaki Disease

How Do You Handle Your Antibodies?

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Science Translational Medicine  04 Jan 2012:
Vol. 4, Issue 115, pp. 115ec2
DOI: 10.1126/scitranslmed.3003627

Although our ability to study human genetics continues to improve, some conditions still fall “between the cracks.” Some rare Mendelian diseases are yielding to large-scale sequencing techniques, and genetic studies of common conditions that are affected by multiple genetic loci have been revolutionized by genome-wide association studies, which leverage large populations and immense statistical power to map complex disease architecture. But what if the disease is both uncommon and potentially multifactorial? This is a tough situation because complex inheritance patterns could make it hard to separate signal from noise in a sequencing study, and assembling a large enough cohort to power a genome-wide association study is difficult. A recent study by Khor et al. provides an example of a successful genetic study of the rare but non-Mendelian condition Kawasaki disease. The researchers solve the above conundrum by assembling a large cohort in a tour de force of worldwide cooperation, which allowed definitive detection of genetic risk factors.

Kawasaki disease is a rare childhood-onset condition that causes inflammation and damage of blood vessels. The coronary arteries can be affected, resulting in aneurismal dilatation and sometimes rupture of these vessels. Both genetic background and infectious triggers are implicated in the pathogenesis of the disease. In the current work, the authors performed a genome-wide association study followed by a large-scale independent replication study. They included over 2000 disease cases and almost 10,000 controls from North America, Europe, Australia, and Asia, conducting the largest study to date of this uncommon disease. Khor et al. identified an association with a coding-change polymorphism in the immunoglobulin receptor gene FCGR2A, which has been reported to alter receptor binding to antibodies. The associated allele has been previously implicated as a risk factor for ulcerative colitis and as a protective factor against systemic lupus erythematosus. The authors also strongly confirm an association with Kawasaki disease in the 19q13 chromosomal region.

Kawasaki disease is frequently treated with intravenous immunoglobulin, but the mechanism of action and reasons for individual variation in response to this treatment are unclear. The association of a particular functional variation in an immunoglobulin receptor with Kawasaki disease should allow us to begin unraveling these important issues, to the benefit of children affected with the disease.

C. C. Khor et al., Genome-wide association study identifies FCGR2A as a susceptibility locus for Kawasaki disease. Nat. Genet. 43, 1241–1246 (2011). [Abstract]

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