Genetic and molecular analyses of HDAC11 in diabetes and its complications

Abstract Diabetes mellitus (DM) and its complications remain major clinical challenges despite advances in prevention and treatment. Histone Deacetylase 11 (HDAC11) has been implicated in glucose metabolism, insulin sensitivity, and inflammatory cytokine (IC) regulation, suggesting potential relevance to diabetes-related phenotypes. This study investigated the associations among genetically proxied lower HDAC11 expression, ICs, and DM-related outcomes. We applied a drug-target Mendelian randomization (MR) framework to evaluate genetically proxied lower HDAC11 expression. The primary analysis used inverse-variance weighting (IVW), with MR-Egger, weighted median, simple mode, and weighted mode as complementary methods. Robustness was evaluated using heterogeneity tests, MR-Egger intercept tests, leave-one-out analysis, and MR-PRESSO. Two-step MR was used to assess IC-mediated pathways. Colocalization analysis assessed whether HDAC11 eQTL and diabetes-related outcome signals shared a causal variant. Protein-protein interaction (PPI) analysis and molecular docking explored potential molecular links. The primary instrument retained eight single-nucleotide polymorphisms (SNPs). Genetically proxied lower HDAC11 expression was associated with lower odds of diabetic ketoacidosis, diabetic nephropathy, and type 2 diabetes and with higher odds of diabetic neuropathy; associations with diabetic maculopathy and diabetic retinopathy were not statistically significant. Effect directions were generally consistent under stricter LD clumping, although statistical support weakened as fewer variants were retained. Heterogeneity tests, MR-Egger intercept analyses, and MR-PRESSO did not detect substantial heterogeneity or horizontal pleiotropy. Colocalization provided low support for shared causal variants. ICs, including IL-2, IL-10, IL-13, and IL-18, showed evidence of potential direction-consistent mediation, whereas selected ICs showed opposite-direction or suppressive pathways. PPI and molecular docking analyses identified HDAC11-related molecular relationships for further study. These analyses identify hypothesis-generating associations between genetically proxied lower HDAC11 expression and selected diabetes-related outcomes. Inflammatory pathways provide candidate mechanisms, while threshold-dependent estimates and limited colocalization support motivate tissue-relevant studies of HDAC11 biology and inhibition.