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Sex-Specific Susceptibility Loci Associated With Coronary Artery Aneurysms in Patients With Kawasaki Disease
Jae-Jung Kim1, Young Mi Hong2, Sin Weon Yun3
1Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Insights
This study identified sex-specific genetic loci associated with coronary artery aneurysms (CAAs) in children with Kawasaki disease (KD). The findings reveal distinct genetic factors influencing CAA development in males and females with KD.
Area of Science:
- Genetics
- Pediatric Vasculitis
- Genomics
Background:
- Kawasaki disease (KD) is a leading cause of acquired heart disease in children.
- Coronary artery aneurysms (CAAs) develop in 20-25% of untreated KD patients, with higher prevalence in males.
- Understanding sex-specific genetic factors for CAA susceptibility in KD is crucial.
Purpose of the Study:
- To identify sex-specific genetic susceptibility loci for coronary artery aneurysms (CAAs) in patients with Kawasaki disease (KD).
- To investigate the genetic basis of differential CAA risk between male and female KD patients.
Main Methods:
- A sex-stratified genome-wide association study (GWAS) was conducted.
- Data from 296 KD patients were analyzed, with replication in an independent cohort of 976 KD patients.
- Cases (KD patients with CAAs) were compared to controls (KD patients without CAAs).
Main Results:
- Six male-specific susceptibility loci (PDE1C, NOS3, DLG2, CPNE8, FUNDC1, GABRQ) were significantly associated with CAAs in KD.
- Two female-specific susceptibility loci (SMAD3, IL1RAPL1) were also significantly associated with CAAs in KD.
- The number of CAA risk alleles showed an additive effect on CAA development.
Conclusions:
- A sex-stratified GWAS successfully identified distinct genetic loci predisposing males and females to CAAs in Kawasaki disease.
- These findings highlight the importance of sex-specific genetic factors in KD pathogenesis and CAA development.
- The identified loci offer potential targets for future research and therapeutic strategies.
Background And Objectives:
Kawasaki disease (KD) is an acute vasculitis that primarily affects children under age 5 years. Approximately 20-25% of untreated children with KD and 3-5% of those treated with intravenous immunoglobulin therapy develop coronary artery aneurysms (CAAs). The prevalence of CAAs is much higher in male than in female patients with KD, but the underlying factors contributing to susceptibility to CAAs in patients with KD remain unclear. This study aimed to identify sex-specific susceptibility loci associated with CAAs in KD patients.
Methods:
A sex-stratified genome-wide association study (GWAS) was performed using previously obtained GWAS data from 296 KD patients and a new replication study in an independent set of 976 KD patients by comparing KD patients without CAA (controls) and KD patients with aneurysms (internal diameter ≥5 mm) (cases).
Results:
Six male-specific susceptibility loci, PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ (odds ratios [ORs], 2.25-9.98; p=0.00204-1.96×10-6), and 2 female-specific susceptibility loci, SMAD3 (OR, 4.59; p=0.00016) and IL1RAPL1 (OR, 4.35; p=0.00026), were significantly associated with CAAs in patients with KD. In addition, the numbers of CAA risk alleles additively contributed to the development of CAAs in patients with KD.
Conclusions:
A sex-stratified GWAS identified 6 male-specific (PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ) and 2 female-specific (SMAD3 and IL1RAPL1) CAA susceptibility loci in patients with KD.
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