title: Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease.
abstract: Kawasaki disease (KD) is an enigmatic, self-limited vasculitis of childhood that is complicated by development of coronary-artery aneurysms. The high incidence of KD in Asian versus European populations prompted a search for genetic polymorphisms that are differentially distributed among these populations and that influence KD susceptibility. Here, we demonstrate a striking, inverse relationship between the worldwide distribution of CCR5- Delta 32 allele and the incidence of KD. In 164 KD patient-parent trios, 4 CCR5 haplotypes including the CCR5- Delta 32 allele were differentially transmitted from heterozygous parents to affected children. However, the magnitude of the reduced risk of KD associated with the CCR5- Delta 32 allele and certain CCR5 haplotypes was significantly greater in individuals who also possessed a high copy number of the gene encoding CCL3L1, the most potent CCR5 ligand. These findings, derived from the largest genetic study of any systemic vasculitis, suggest a central role of CCR5-CCL3L1 gene-gene interactions in KD susceptibility and the importance of gene modifiers in infectious diseases.
authors.affiliation: Department of Pediatrics, University of California at San Diego School of Medicine, La Jolla 92093-0830, USA.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Burns
authors.forename: Chisato
authors.initials: C
authors.lastname: Shimizu
authors.forename: Enrique
authors.initials: E
authors.lastname: Gonzalez
authors.forename: Hemant
authors.initials: H
authors.lastname: Kulkarni
authors.forename: Sukeshi
authors.initials: S
authors.lastname: Patel
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shike
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sundel
authors.forename: Jane W
authors.initials: JW
authors.lastname: Newburger
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Ahuja
mesh_terms: D019742:Chemokines, CC / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006580:Genetic Carrier Screening; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D008297:Male; D008957:Models, Genetic; D009080:Mucocutaneous Lymph Node Syndrome / Q000235:genetics* / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics*; D014657:Vasculitis / Q000235:genetics / Q000276:immunology
chemical_list: C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D005819:Genetic Markers; D016756:Immunoglobulins, Intravenous; D019713:Receptors, CCR5