Male-specific association of the <i>FCGR2A</i> His167Arg polymorphism with Kawasaki disease

<div><p>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 <i>FCGR2A</i> [odds ratio (OR) = 1.40, <i>P</i> = 9.31 × 10⁻⁵], rs12516652 in <i>SEMA6A</i> (OR = 1.87, <i>P</i> = 3.12 × 10⁻⁴), and rs5771303 near <i>IL17REL</i> (OR = 1.57, <i>P</i> = 2.53 × 10⁻⁵). The male-specific association of <i>FCGR2A</i>, but not <i>SEMA6A</i> and <i>IL17REL</i>, was also replicated in a Japanese population (OR = 1.74, <i>P</i> = 1.04 × 10⁻⁴ in males vs. OR = 1.22, <i>P</i> = 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 <i>FCGR2A</i> was confirmed in males (OR = 1.48, <i>P</i> = 1.43 × 10⁻⁷), but not in the females (OR = 1.17, <i>P</i> = 0.055). The present study demonstrates that p.His167Arg, a KD-associated <i>FCGR2A</i> variant, acts as a susceptibility gene in males only. Overall, the gender differences associated with <i>FCGR2A</i> in KD provide a new insight into KD susceptibility.</p>