Abstract
BackgroundThe etiology of Kawasaki Disease (KD) is enigmatic, although an infectious cause is suspected. Polymorphisms in CC chemokine receptor 5 (CCR5) and/or its potent ligand CCL3L1 influence KD susceptibility in US, European and Korean populations. However, the influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown.Methodology/Principal FindingsWe used unconditional logistic regression analyses to determine the associations of the copy number of the CCL3L1 gene-containing duplication and CCR2-CCR5 haplotypes in 133 Japanese KD cases [33 with CAL and 25 with resistance to IVIG] and 312 Japanese controls without a history of KD. We observed that the deviation from the population average of four CCL3L1 copies (i.e., < or > four copies) was associated with an increased risk of KD and IVIG resistance (adjusted odds ratio (OR) = 2.25, p = 0.004 and OR = 6.26, p = 0.089, respectively). Heterozygosity for the CCR5 HHF*2 haplotype was associated with a reduced risk of both IVIG resistance (OR = 0.21, p = 0.026) and CAL development (OR = 0.44, p = 0.071).Conclusions/SignificanceThe CCL3L1-CCR5 axis may play an important role in KD pathogenesis. In addition to clinical and laboratory parameters, genetic markers may also predict risk of CAL and resistance to IVIG.
Highlights
Kawasaki disease (KD) is an acute, self-limiting systemic vasculitis of infants and children [1,2]
The most serious complication of Kawasaki Disease (KD) is the development of coronary artery lesions (CAL) that range from transient dilatation to destruction of the vessel wall architecture resulting in aneurysms [3]
Our results suggest that in Japanese children, copy number variation of the segmental duplication bearing CC ligand 3 like 1 (CCL3L1) associates with susceptibility to KD and intravenous immunoglobulin (IVIG) response whereas the CCR264I-containing chemokine receptor 5 (CCR5)-HHF*2 haplotype is associated with a reduced risk of both CAL development and IVIG resistance
Summary
Kawasaki disease (KD) is an acute, self-limiting systemic vasculitis of infants and children [1,2]. Administration of a combination of a high dose intravenous immunoglobulin (IVIG) and aspirin is the standard therapy for acute KD, 15–30% of KD patients have persistent or recurrent fever after IVIG treatment [4,5,6,7,8,9,10]. Such patients are at increased risk of developing CAL [11]. The influence of these variations on KD susceptibility, coronary artery lesions (CAL) and response to intravenous immunoglobulin (IVIG) in Japanese children, who have the highest incidence of KD, is unknown
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