Genetic Variations in the Receptor‐Ligand PairCCR5andCCL3L1Are 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.

Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases

“…In previous studies, we found that the copy number of CCL3L1 modified the Kawasaki disease-, SLE-and HIV-1-disease-influencing effects of CCR5 haplotypes (Burns et al, 10 Mamtani et al 11 and data not shown). Thus, here we sought to determine whether the underlying copy number of CCL3L1 modified the SLE-and SS-influencing effects associated with FCGR3B CNVs.…”

“…[1][2][3][4] It is to be noted that there seems to be an enrichment of CNV in immune response genes 1 such that they may contribute to the observed inter-individual variability in susceptibility to infectious diseases, vasculitis and autoimmune diseases. For example, we and others found that the copy number of segmental duplication on chromosome 17q that contains the gene encoding the chemokine CC chemokine ligand 3-like 1 (CCL3L1) influences HIV-AIDS susceptibility, [5][6][7][8][9] and the risk of developing Kawasaki's disease, 10 systemic lupus erythematosus (SLE) 11 and rheumatoid arthritis (RA). 12 CNV in the gene encoding the complement component C4 and FCGR2C has been associated with SLE 13 and idiopathic thrombocytopenic purpura, 14 respectively.…”

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease

“…Burns et al [15] have also reported about genetic variation in CCR5 and susceptibility to KD, demonstrating an inverse relationship between the worldwide distribution of CCR5-D32 allele and the incidence of KD. In a large familybased study using transmission disequilibrium test (TDT) analyses, an asymmetric transmission of the CCR5-D32 allele from 46 heterozygous parents to their affected children is observed, supporting the hypothesis that the CCR5-D32 allele might protect against development of KD.…”

“…For instance, in European populations the average allele frequency is estimated to be 10%, whereas in Asian populations the 32-bp deletion is rare [14]. Moreover, Burns et al report about a striking, inverse relationship between the worldwide distribution of the CCR5-D32 allele and the incidence of KD [15]. They state that genetic variation in CCR5 plays an influential role in KD susceptibility but that the results need to be confirmed in an independent cohort.…”

Relationship between T-cell HLA-DR expression and intravenous immunoglobulin treatment response in Kawasaki disease

“…This triggered activation, in turn, starts a systemic immune response leading to uncontrolled inflammation and vasculitis in genetically susceptible patients (9)(10)(11). Although a number of previous studies have sought to determine the cause of this disease, very few have addressed the role of the different peripheral T-cell populations in the acute phase of KD or in the effectiveness of IVIG treatment (12,13).…”