Sex-Specific Susceptibility Loci Associated With Coronary Artery Aneurysms in Patients With Kawasaki Disease

Jae-Jung Kim; Young Mi Hong; Sin Weon Yun; Kyung-Yil Lee; Kyung Lim Yoon; Myung-Ki Han; Gi Beom Kim; Hong-Ryang Kil; Min Seob Song; Hyoung Doo Lee; Kee Soo Ha; Hyun Ok Jun; Jeong Jin Yu; Gi Young Jang; Jong-Keuk Lee; Korean Kawasaki Disease Genetics Consortium

doi:10.4070/kcj.2023.0244

Sex-Specific Susceptibility Loci Associated With Coronary Artery Aneurysms in Patients With Kawasaki Disease

Korean Circ J. 2024 Apr 8. doi: 10.4070/kcj.2023.0244. Online ahead of print.

Authors

Affiliations

¹ Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
² Department of Pediatrics, Ewha Womans University Hospital, Seoul, Korea.
³ Department of Pediatrics, Chung-Ang University Hospital, Seoul, Korea.
⁴ Department of Pediatrics, Daejeon St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
⁵ Department of Pediatrics, Kyung Hee University Hospital at Gangdong, Seoul, Korea.
⁶ Department of Pediatrics, Gangneung Asan Hospital, University of Ulsan, Gangneung, Korea.
⁷ Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.
⁸ Department of Pediatrics, Chungnam National University Hospital, Daejeon, Korea.
⁹ Department of Pediatrics, Inje University Paik Hospital, Busan, Korea.
¹⁰ Department of Pediatrics, Pusan National University Hospital, Busan, Korea.
¹¹ Department of Pediatrics, Korea University Guro Hospital, Guro, Korea.
¹² Department of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea.
¹³ Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
¹⁴ Department of Pediatrics, Korea University Ansan Hospital, Ansan, Korea.
¹⁵ Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. cookie_jklee@hotmail.com.

^# Contributed equally.

PMID: 38767439
DOI: 10.4070/kcj.2023.0244

Abstract

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.

Keywords: Coronary aneurysm; Genome-wide association study; Mucocutaneous lymph node syndrome; Sex.

Abstract

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