Male-specific association of the FCGR2A His167Arg polymorphism with Kawasaki disease

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.

Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits

“…Very few studies addressing gene-by-sex interactions at the level of cardio-metabolic phenotypes have been reported (Andreux et al, 2012;Dimas et al, 2012;Liu et al, 2012a;Myers et al, 2014;Rawlik et al, 2016). In general, sex differences in the genetic architecture of human disease (Afshari et al, 2017;Chen et al, 2018;Kwon et al, 2017;Lu et al, 2017) and anthropometric traits (Karp et al, 2017;Kukurba et al, 2016;Nookaew et al, 2013;Palmer and Clegg, 2014;Randall et al, 2013;Weiss et al, 2006;White and Tchoukalova, 2014) are suggested by some studies, yet others failed to find evidence for prevalent sex-specific genetic associations in mouse and human (Krohn et al, 2014). Our results clearly indicate that gene-by-sex interactions are common in mice, at least for metabolic traits.…”

CD32a polymorphism rs1801274 affects the risk of Kawasaki disease

“…Besides, Lou and colleagues exhibited nominally reducing tendency for AG þ GG vs. AA and GG vs. AA in their study [26]. While Kwon and colleagues claimed that significant correlation of the polymorphism with KD onset only appeared in males, not among females [29]. Nonetheless, some other researches detected no distinct influence for the polymorphism rs1801274 on KD occurrence at all [20,21,25].…”

“…Consequently, in IgG2-mediated phagocytosis, individuals carrying AA genotype would show higher efficiency than those with GG genotype. And altered genotype of the polymorphism rs1801274 could cause insufficient elimination of immune complexes whose depositions on vascular walls might further result in vascular diseases [29]. Besides, earlier reports have suggested potential connection for this polymorphism with some inflammatory diseases and autoimmune diseases, such as systemic lupus erythemathosus, inflammatory bowel disease and rheumatoid arthritis [32][33][34].…”

“…During the fulltext screening, 14 more publications were further omitted for not conforming to our inclusion criteria. As a result, 11 eligible reports were ultimately encompassed into this meta- analysis [19][20][21][22][23][24][25][26][27][28][29], containing 17 independent studies. Of the studies, 13 were on Asian populations while only 4 on Caucasians.…”

Association between the miRNA‐149 rs2292832 T>C polymorphism and Kawasaki disease susceptibility in a southern Chinese population

“…In the first genome‐wide association study (GWAS) for KD, variants of several genes (such as lnx1 , CAMK2D , ZFHX3 , CSMD1 , and tcp1 ) were suggested to be associated with KD susceptibility . In addition, SNPs in rs2254546, rs2857151, rs4813003, rs16921209, rs7922552, rs17076896, rs12068753, rs4786091, and rs2833195 and some SNPs in BLK , CD40 , and FCGR2A may be relevant to susceptibility, clinical presentations (such as CAA and CAL), laboratory data (such as CRP), treatment of KD, and gender in KD in GWASs …”