Multiomics Mendelian Randomization Identifies Lactylation-Related Molecular Traits in Type 1 Diabetes

Lactylation is a posttranslational modification involved in cellular metabolic and immune processes. Although dysregulated lactate metabolism has been implicated in type 1 diabetes (T1D), the genetic relevance of lactylation-related molecular traits remains poorly defined.

Summary-data-based Mendelian randomization (SMR) was applied to integrate blood-derived methylation/expression/protein quantitative trait loci (mQTLs/eQTLs/pQTLs) for 353 lactylation-related genes with a T1D genome-wide association study (7467 cases and 10,218 controls). The HEIDI test evaluated heterogeneity. Shared genetic signals were assessed by Bayesian colocalization. Associations identified in the discovery analysis were replicated in the FinnGen_R12_T1D and FinnGen_R9_E4_DM1NEU cohorts. mQTL-eQTL SMR analysis evaluated methylation-expression regulatory relationships. Steiger directionality testing and GTEx tissue eQTL analyses were performed for prioritized genes.

SMR prioritized PDAP1, PNKD, and HMGB1 as candidate genes associated with T1D. At the DNA methylation level, methylation at cg05715492 (PDAP1) was positively associated with T1D risk (OR = 1.29, 95% CI: 1.09-1.53), whereas cg05991184 (PNKD) showed an inverse association (OR = 0.73, 95% CI: 0.59-0.90). cg22712983, cg26786924, and cg04880052 in PNKD exhibited positive associations. cg25251738 (HMGB1) methylation was inversely associated with risk (OR = 0.85, 95% CI: 0.75-0.97). At the expression level, genetically predicted PDAP1 (OR = 0.26, 95% CI: 0.10-0.66) and HMGB1 (OR = 0.45, 95% CI: 0.22-0.91) expressions were inversely associated with T1D risk, whereas PNKD expression was positively associated (OR = 1.13, 95% CI: 1.04-1.23). mQTL-eQTL SMR analyses demonstrated significant methylation-expression associations at PDAP1, PNKD, and HMGB1 loci. Steiger directionality testing supported the observed associations. In GTEx datasets, higher PNKD expression was associated with increased T1D risk in both whole blood and spleen.

PNKD, PDAP1, and HMGB1 were prioritized as lactylation-related candidate genes associated with T1D risk through integrated genetic analyses. This finding generates hypothesis for future investigations into the potential involvement of lactylation-related pathways in T1D pathogenesis.