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PubMed2026

Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.

CONTEXT: Oligogenic inheritance in maturity-onset diabetes of the young (MODY) remains poorly characterized, and the contribution of multiple candidate variants to disease pathogenesis is incompletely understood. OBJECTIVE: To investigate the pathogenicity and mechanistic contribution of multiple MODY gene variants identified in a MODY-like family and determine their role in early-onset diabetes. METHODS: Comprehensive genetic analysis of known MODY genes was performed in a MODY-like family. Functional effects of HNF1A and HNF1B variants were assessed using luciferase reporter assays in HEK293T cells. Functional characterization of ABCC8 variants included Kir6.2-dependent thallium (Tl+) flux assays, sulfonylurea responsiveness, and channel stability. RESULTS: Four variants in 3 MODY genes were identified in the proband: novel HNF1A p.Ser551Lysfs*2, HNF1B p.Glu102Ala, and ABCC8 p.Arg298Cys and p.Arg521Gln. Functional analysis showed that HNF1A p.Ser551Lysfs*2 retained approximately 5% of wild-type transactivation activity, consistent with loss-of-function, whereas HNF1B p.Glu102Ala and ABCC8 p.Arg521Gln exhibited wild-type-like function. In contrast, ABCC8 p.Arg298Cys reduced channel activity to 77% of wild-type levels while preserving sulfonylurea responsiveness. Segregation analysis identified HNF1A p.Ser551Lysfs*2 and ABCC8 p.Arg298Cys in affected parents. The proband, who inherited both pathogenic variants, developed diabetes earlier than either parent and was exposed to maternal hyperglycemia in utero, which may also have contributed to this early onset. CONCLUSION: Functional characterization distinguishes pathogenic from variants of unknown significance and supports digenic inheritance of HNF1A and ABCC8. Their additive effects, together with intrauterine hyperglycemia, likely accelerated disease onset. This study provides mechanistic evidence for oligogenic contributions to MODY and expands the genetic architecture of early-onset diabetes.

Humans↗

PubMed2026

Multi-omics integration and colocalization analyses prioritize candidate molecular loci associated with hypothermia.

BACKGROUND: Hypothermia is a life-threatening condition lacking specific pharmacological treatments. This study aimed to prioritize genetically supported molecular loci associated with hypothermia and to explore their pharmacological tractability using multi-omics data. METHODS: Initially, 2532 druggable genes were curated from the Drug-Gene Interaction Database and established literature. These were cross-referenced with cis-eQTL and cis-pQTL datasets, encompassing 870,655 and 114,281 SNPs for blood, respectively, alongside 2379 shared SNPs across adipose, skeletal muscle, and heart tissues. Matched instrumental variables were integrated with hypothermia GWAS summary statistics for two-sample Mendelian randomization (MR) and Bayesian colocalization. Transcriptomic differential expression analysis (DEA) was subsequently conducted as an exploratory analysis of cold-exposure-associated expression changes. Database-derived compound annotations were systematically re-evaluated according to target specificity, established pharmacological mechanism, and concordance with the direction of the MR estimates. RESULTS: Among 671 gene-level MR tests, 36 genes reached nominal significance, whereas only ABCC8 remained significant after FDR correction. Colocalization was evaluable for 8 of these 36 genes, and 4 loci (COL18A1, SLC1A7, ADIPOQ, and MERTK) met the prespecified PP.H4>0.90 threshold. The remaining 28 loci were not evaluable because sufficient overlapping regional variants were unavailable after harmonization. Transcriptomic analysis identified altered expression of SLC1A3 and SLCO4A1 under cold exposure, although these findings did not directly validate the colocalization-supported loci. Re-evaluation of database-derived compound annotations did not identify any direct, selective, and directionally concordant drug-repurposing candidate for hypothermia. CONCLUSIONS: COL18A1, SLC1A7, ADIPOQ, and MERTK showed colocalization support among the 8 evaluable nominal MR-associated loci. Because colocalization coverage was limited, these genes should be regarded as preliminary candidate loci rather than established therapeutic targets. The pharmacological annotations were indirect, non-selective, unsupported, or directionally inconsistent and should be interpreted solely as hypothesis-generating information.

Bayesian colocalization↗

PubMed2026

Glycemic and Renal Effects of SGLT2 Inhibitors in Monogenic Diabetes: A Real-World National Study.

AIMS: Evidence regarding the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in monogenic diabetes is limited. We evaluated real-world metabolic, renal, and safety outcomes of SGLT2i therapy in adults with monogenic diabetes. MATERIALS AND METHODS: This multicenter retrospective study included adults with genetically confirmed monogenic diabetes treated with SGLT2i. Clinical and biological data were collected at baseline and after approximately 1 and 2 years. Longitudinal changes were analysed using linear mixed-effects models adjusted for baseline value, age, and sex and treatment intensification. RESULTS: Forty patients (mean age 48.6 ± 15.2 years) with MIDD (n = 16), HNF1B-MODY (n = 9), HNF1A/HNF4A-MODY (n = 11), or other MODY subtypes (ABCC8, INS, RFX6; n = 4) were followed for 23.9 ± 5.9 months. HbA1c remained stable overall but decreased significantly in patients with baseline HbA1c ≥ 8% (9.6% ± 1.3% to 7.6% ± 0.7%; p = 0.001). UACR declined significantly (-35.6% at 1 year and -43.5% at 2 years; p = 0.004), particularly in those with baseline CKD (trend). Genotype-specific trends suggested greater glycemic improvement in HNF1A/HNF4A-MODY and greater UACR reduction in MIDD. eGFR declined modestly over time. Non-serious adverse events occurred in 15% of patients, 7.5% discontinued treatment, and no ketoacidosis, acute kidney injury, or deaths were reported. CONCLUSIONS: In this nationwide cohort of patients with monogenic diabetes-the largest reported to date-SGLT2i therapy was associated with improved glycemic control in individuals with baseline HbA1c ≥ 8%, reduced albuminuria, and showed a favourable safety profile. These findings support SGLT2i as a potential therapeutic option that warrants confirmation in larger controlled studies.

Humans↗

PubMed2026

Genetic Determinants of Pulmonary Artery Size in over 50,000 Subjects with and without COPD.

RATIONALE: Pulmonary artery (PA) enlargement is a non-invasive imaging biomarker associated with pulmonary hypertension and mortality in COPD; however, its genetic determinants remain incompletely understood. OBJECTIVES: To characterize the genetic architecture of PA size across COPD-enriched and population-based cohorts. METHODS: We performed genome-wide association analyses of PA diameter using whole-genome sequencing in COPDGene (n=9,418) and ECLIPSE (n=1,859), and imputed-genotype data from the UK Biobank (n=37,073). We replicated lead variants in the Framingham Heart Study (FHS; n=3,289), incorporated all four studies into a joint meta-analysis, and identified independent signals through conditional analyses. Candidate effector genes were prioritized using coding variant annotation, colocalization, and integrative regulatory evidence. MEASUREMENTS AND MAIN RESULTS: We identified 44 independent genome-wide significant PA diameter signals within 39 loci, including 8 variants replicated in FHS, novel associations near FRMD4B, SLC20A2, BORCS7-ASMT, and KCNRG, and 5 signals in conditional analysis including multiple signals at ANO1. Genetic effects were concordant across imaging modalities and cohorts of differing COPD burden. Effector-gene prioritization nominated ABCC8, PDGFD, HMCN1, CCNE1, and TBX20, implicating pathways in vascular remodeling, developmental regulation, smooth muscle and endothelial function, ion-channel signaling, and extracellular matrix organization. Colocalization with pulse pressure GWAS demonstrated substantial shared causal variation between pulmonary and systemic vascular biology. CONCLUSIONS: In this largest genetic study of pulmonary vascular imaging to date, PA diameter exhibits a polygenic architecture consistent across imaging modalities and cohorts of differing COPD burden. The prioritized effector genes bridge rare-variant pulmonary hypertension biology with common-variant systemic vascular biology.

Pulmonary artery diameter↗