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Abstract
Kawasaki disease (KD) is an acute systemic vasculitis that can potentially cause coronary artery aneurysms in some children. KD occurs approximately 1.5 times more frequently in males than in females. To identify sex-specific genetic variants that are involved in KD pathogenesis in children, we performed a sex-stratified genome-wide association study (GWAS), using the Illumina HumanOmni1-Quad BeadChip data (249 cases and 1,000 controls) and a replication study for the 34 sex-specific candidate SNPs in an independent sample set (671 cases and 3,553 controls). Male-specific associations were detected in three common variants: rs1801274 in FCGR2A [odds ratio (OR) = 1.40, P = 9.31 × 10−5], rs12516652 in SEMA6A (OR = 1.87, P = 3.12 × 10−4), and rs5771303 near IL17REL (OR = 1.57, P = 2.53 × 10−5). The male-specific association of FCGR2A, but not SEMA6A and IL17REL, was also replicated in a Japanese population (OR = 1.74, P = 1.04 × 10−4 in males vs. OR = 1.22, P = 0.191 in females). In a meta-analysis with 1,461 cases and 5,302 controls, a very strong association of KD with the nonsynonymous SNP rs1801274 (p.His167Arg, previously assigned as p.His131Arg) in FCGR2A was confirmed in males (OR = 1.48, P = 1.43 × 10−7), but not in the females (OR = 1.17, P = 0.055). The present study demonstrates that p.His167Arg, a KD-associated FCGR2A variant, acts as a susceptibility gene in males only. Overall, the gender differences associated with FCGR2A in KD provide a new insight into KD susceptibility.
Highlights
Recent studies have shown that sex-related differences in the genetic architecture may contribute to complex diseases that are more prevalent in one sex over the other in the general population [1]
To identify sex-specific genetic variants associated with Kawasaki disease (KD), we carried out sex-stratified genome-wide association study (GWAS), using data from 249 cases (165 males and 84 females) and 1,000 control subjects (783 males and 217 females) that were genotyped with the Illumina Omni1-Quad BeadChip
A total of 34 sex-specific candidate Single nucleotide polymorphism (SNP) that are associated with KD were chosen for a replication study in an independent sample set consisting of 666 patients with KD (385 males and 281 females) and 3,553 control subjects (1,079 males and 2,474 females)
Summary
Recent studies have shown that sex-related differences in the genetic architecture may contribute to complex diseases that are more prevalent in one sex over the other in the general population [1]. Autoimmune diseases, such as systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis, occur more frequently in women than in men [2]. Males were predominantly more susceptible to many infectious diseases than females, and antibody responses against viral vaccines were higher in females than in males [6,7,8,9]. There are differences in the incidence of many infectious or autoimmune diseases by gender, the mechanism remains unknown
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