An endoplasmic reticulum stress gene module is associated with intravenous immunoglobulin resistance in Kawasaki disease

Intravenous immunoglobulin (IVIG) resistance affects 10% to 20% of children with Kawasaki disease (KD) and is associated with an elevated risk of coronary artery lesions. The molecular basis of this treatment failure remains poorly defined. In this study, we sought to identify gene expression signatures associated with IVIG resistance. We analyzed gene expression data from 171 children with acute KD (61 IVIG-resistant and 110 IVIG-sensitive) from the GSE63881 dataset. We used weighted gene co‑expression network analysis (WGCNA) to identify modules correlated with IVIG resistance, and then performed functional enrichment analysis to characterize the biological processes enriched among the module genes. Clinical characteristics were compared between the two groups. We identified 18 co‑expression modules. Module ME17 showed the strongest correlation with IVIG resistance ( r = − 0.20, P = 0.008), and its constituent genes were consistently downregulated in resistant children. ME17 contained 36 genes that showed enrichment for response to endoplasmic reticulum (ER) stress (GO:0034976, adjusted P = 0.009), ATF6-mediated unfolded protein response (GO:0036500, adjusted P = 0.012), and protein folding (GO:0006457, adjusted P = 0.029). Eight core genes—MZB1, CAV1, TXNDC5, FKBP11, POU2AF1, PDIA5, ABCB9, and CD38—were all downregulated in resistant children. Clinically, resistant children had a significantly higher rate of coronary artery lesions than sensitive children (24.6% vs. 4.5%, P < 0.001). A 36‑gene co‑expression module enriched in ER stress and protein folding pathways was associated with IVIG resistance in this KD cohort. These eight core genes represent potential molecular correlates of treatment response and merit further investigation as candidate biomarkers for risk stratification.