Genetic liability to childhood Kawasaki disease and adult cardiovascular outcomes

Mengzhuo Wang, Sha Lin, Xiaoliang Liu, Jinlin Wu, Yifei Li

Background Kawasaki disease (KD) occurring in childhood has been epidemiologically associated with increased adult cardiovascular risk, particularly in children who develop coronary aneurysms during the acute phase. However, the causal nature of this association remains uncertain. This study employed genetic causal association analysis to investigate potential causal effects of KD on adult-onset cardiovascular complications. This study provides new data from our cohort, representing the largest sample size for a KD genome-wide association study (GWAS) analysis and has not been reported before. Methods We first enrolled a prospective KD cohort of 316 patients who received whole-exome sequencing (WES) analysis. We then performed a GWAS analysis and conducted further analyses using summary-level statistics from the IEU Open GWAS database, the GWAS Catalog, and our East Asian KD cohorts. The inverse variance weighted (IVW) method served as the primary analytical approach. All analyses were performed using R software. Results We established the largest WES-based KD cohort to date, with 316 children receiving WES and GWAS analyses. Then, in the following assessment, no significant causal associations were observed between KD and major adult cardiovascular outcomes. Replication analyses in European populations revealed modest evidence of potential causal associations with specific conditions. The IVW method indicated weak causal associations with ventricular arrhythmia (OR = 1.0296, 95% CI = 1.0037–1.0562, P = 0.025) and chronic heart failure (OR = 1.0110, 95% CI = 1.0007–1.0213, P = 0.0354) in particular traits. However, neither association was reproduced across independent GWAS datasets or corroborated by sensitivity analyses; therefore, these observations should be regarded as exploratory. Conclusion This analysis provides genetic evidence that does not support a strong causal relationship between childhood KD and an increased risk of most adult cardiovascular diseases. Given the limited KD GWAS sample sizes and relaxed instrument-selection thresholds, these findings should be interpreted cautiously. However, they do not exclude clinically important long-term cardiovascular sequelae in patients with coronary artery involvement after KD.