Investigating the causal role of the pediatric plasma proteome in Kawasaki disease: a Mendelian randomization study

Abstract Background Kawasaki Disease (KD), a leading pediatric cause of acquired heart disease with an unknown etiology, necessitates the identification of causal biological factors. This study employed Mendelian Randomization (MR) using novel pediatric plasma protein quantitative trait loci (pQTLs) to identify proteins suggestively causally linked to KD risk. Methods Genetic instruments for 443 plasma proteins (from 2,147 Danish children/adolescents) and KD GWAS data (European ancestry; 479 cases/490,361 controls) were used in a two-sample MR design. Analyses included univariable MR (UVMR) with nine robust techniques, multivariable MR (MVMR) with five distinct methods, and protein–protein interaction (PPI) analyses. Results Consistent suggestive MR findings included a strong negative UVMR association for IGFBP3 with KD risk (across eight robust methods). MVMR (five methods) further linked FCGR3B, PLEK, AZGP1, and THAP5 to decreased risk, and SLIT1, FGB, CFH, and SELP to increased risk. PPI analysis implicated complement/coagulation cascades. Conclusions This study, leveraging novel pediatric pQTL data, identifies several plasma proteins with potential causal roles in KD, highlighting critical pathways. These suggestive findings enhance understanding of KD in children and suggest promising avenues for future biomarker and therapeutic development.