Joseph H Breeyear | PubMed Health

PubMed2026

Disentangling Sex Differences in Sulfonylurea Drug Response With Genome-Wide Association Studies in Individuals With Type 2 Diabetes.

Sulfonylureas are a cornerstone of type 2 diabetes therapy despite interindividual variability in response. Despite well-documented sex-based differences, pharmacogenomic and genome-wide association studies (GWAS) have largely overlooked sex as a biological variable. We conducted the first sex-stratified GWAS of hemoglobin A1c (HbA1c) response to sulfonylureas in Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial participants (N = 871). Variants meeting genome-wide (P < 5.0 × 10-8) and suggestive (P < 5.0 × 10-6) significance were assessed for replication in the Pharmacogenomics of Metformin (PMET1) cohort. Replicated variants were further analyzed in the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) cohort to assess acute insulin and glucose responses to a single glipizide dose. Genome-wide significant loci with sex-specific effects were identified: KAZN, KIF2B, SLC39A10, and SPINK5 (combined-sex); CRACR2A, KCNK2, and TENM2 (male-only); and NACPH2 (female-only). Two suggestive variants in the TMEM64/NECAB1 locus, associated with reduced HbA1c response to sulfonylureas in the male-only ACCORD analysis, were directly replicated in the PMET1 male-only cohort. In SUGAR-MGH, one replicated variant (rs6471250-C) was significantly associated with reduced peak insulin in males (P = 0.035) but not females (P = 0.40), demonstrating sex-specific functional effects. This study identified statistically supported and biologically plausible loci with prior evidence linking nearby genes to pathways relevant to sulfonylurea action, including insulin secretion, insulin regulation/sensitivity, calcium signaling, potassium-channel biology, and glucose transport. The findings highlight sex-specific differences in sulfonylurea response, providing mechanistic insights and underscoring the importance of sex-specific precision medicine. Identification of genetic variants influencing sex-specific response could inform dosing to optimize sulfonylureas.

Humans↗

PubMed2025

Genomics-informed drug-repurposing strategy identifies two therapeutic targets for preventing liver disease associated with metabolic dysfunction.

Identification of drug-repurposing targets with genetic and biological support is an economically and temporally efficient strategy for improving the treatment of diseases. We employed a cross-disciplinary approach to identify potential therapeutics for the prevention of metabolic-dysfunction-associated steatotic liver disease (MASLD) in at-risk individuals by using humans as a model organism. We identified 212 putative candidate genes associated with MASLD by using data from a large multi-ancestry genetic association study, of which 158 (74.5%) were previously unreported. From this set, we identified 57 genes that encode for druggable protein targets and for which the effects of increasing genetically predicted gene expression on MASLD risk align with the function of that drug on the protein target. We then used We then evaluated these potential targets for evidence of efficacy by using Mendelian randomization, pathway analysis, and protein structural modeling. Through these approaches, we present compelling evidence to suggest that the activation of FADS1 by icosapent ethyl, as well as S1PR2 by fingolimod, could be a promising therapeutic strategy for MASLD prevention.

Humans↗