Genetic predisposition to Kawasaki disease and the risk of coronary atherosclerosis: a Mendelian randomisation study

Abstract Background: Kawasaki disease is linked to coronary artery abnormalities, yet whether this reflects a direct causal relationship with atherosclerosis remains unclear due to potential confounding factors. This study aimed to investigate, using two-sample Mendelian randomisation, whether a genetic predisposition to Kawasaki disease is associated with subsequent atherosclerosis. Methods: Instrumental variables were single-nucleotide polymorphisms significantly associated with Kawasaki disease from a large-scale genome-wide association study (119 cases, 6071 controls). Summary data for coronary atherosclerosis (the primary outcome), cerebral atherosclerosis, peripheral atherosclerosis, and three non-invasive surrogates (brachial–ankle pulse wave velocity, carotid intima-media thickness, and pulse wave arterial stiffness index) were obtained from independent European and African cohorts. The inverse variance weighted method served as the primary analysis, supported by four sensitivity analyses. Results: Genetically predicted Kawasaki disease showed a suggestive association with an increased risk of coronary atherosclerosis (inverse variance-weighted: odds ratio = 1.0213; 95% confidence interval = 1.0050 to 1.0379; P = 0.01), This direction was consistent across all sensitivity methods, with no evidence of pleiotropy or heterogeneity. No associations were observed for the remaining outcomes. Reverse analysis did not support reverse causality. Conclusions: This study provides evidence that genetic predisposition to Kawasaki disease may be associated with coronary atherosclerosis. Given the limited cohorts, the null findings for other vascular territories are inconclusive. Larger independent Kawasaki disease genome-wide association studies are needed for replication.