Genetic variations in the receptor-ligand pair CCR5 and CCL3L1 are important determinants of susceptibility to Kawasaki disease.
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.
Burns
Jane C
JC
Department of Pediatrics, University of California at San Diego School of Medicine, La Jolla 92093-0830, USA.
Shimizu
Chisato
C
Gonzalez
Enrique
E
Kulkarni
Hemant
H
Patel
Sukeshi
S
Shike
Hiroko
H
Sundel
Robert S
RS
Newburger
Jane W
JW
Ahuja
Sunil K
SK
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
C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D005819:Genetic Markers; D016756:Immunoglobulins, Intravenous; D019713:Receptors, CCR5