Diabetologia

Type 2 diabetes (T2D) affects 11.1% of the global population, underscoring the need for biomarkers that inform treatment response and glycemic outcomes. We evaluated the association between the FTO variant rs9939609-A and glycemic control in a Mexican population. A total of 174 individuals living with T2D from Merida and Sisal, Yucatan, were included, of whom 85% were receiving oral hypoglycemic agents as main treatment. Glycemic control was defined cross-sectionally as good ([≤]130 mg/dL, n=...

Abstract Introduction Cardiovascular disease (CVD) is an important complication of type 2 diabetes (T2D). Current incident CVD-prediction models use single baseline measurements and achieve moderate performance in people with T2D, with C-indices around 0.7. Modern healthcare registries contain repeated measurements of HbA1c, LDL-cholesterol and eGFR, which could carry incremental predictive value. However, the added value of trajectory measures for CVD-risk prediction remains unclear. We aimed t...

ObjectivesTo estimate potential launch prices of generic semaglutide following patent expiry from 2026 and to quantify the global obesity and type 2 diabetes (T2DM) burden in countries where generic access may become possible. MethodsWe used World Bank population data and World Obesity and Diabetes Atlas prevalence estimates to calculate obesity and T2DM burden in countries where semaglutide patents expire in 2026 or were not filed. Patent status was identified using MedsPaL and cross-checked w...

IntroductionGenome-wide association studies (GWAS) for kidney function have mainly focused on creatinine-based glomerular filtration rate (eGFRcrea), which is affected by variation in muscle mass. Moreover, the genetic basis of the sexual dimorphism of chronic kidney disease is underexplored. MethodsWe performed a GWA meta-analysis for creatinine clearance (CrCl), a muscle mass-independent kidney function phenotype, in 58,976 individuals of European descent from the Lifelines Cohort Study. Res...

Acute kidney injury (AKI) and chronic kidney disease (CKD) are two interconnected clinical conditions, both defined by degree of functional impairment, but with heterogeneous clinical trajectories. Using new transcriptomic technologies, recent studies have described the cellular diversity in the healthy and injured kidney at the single cell level. Here, we used single nucleus transcriptomics to investigate the molecular diversity and commonalities in kidney biopsies from over 150 participants wi...

BackgroundA coronary artery calcium (CAC) score of 0 is widely considered to indicate low short- to intermediate-term risk for coronary artery disease (CAD) and is frequently used to defer lipid-lowering therapy. However, a subset of individuals with CAC=0 still experience events, highlighting residual risk not captured by imaging alone. Polygenic risk scores (PRS) quantify lifelong inherited susceptibility, but conventional approaches rely on predefined ancestry labels despite human genetic div...

Individuals with chronic kidney disease (CKD) have higher rates of hip fracture and post-fracture mortality. Although they may develop age-related osteoporosis similar to those without CKD, they may also exhibit CKD-related metabolic bone disease (MBD), characterized by low, high, or mixed turnover at similar levels of bone mineral density (BMD). Because BMD does not provide information about turnover status, clinical decision-making is challenging. This study evaluated the associations between ...

BackgroundDiabetes mellitus (DM) remains a major global health challenge and is associated with vision-threatening complications, including diabetic macular edema (DME), a leading cause of visual impairment. Dyslipidemia has been implicated in the development of macular edema through mechanisms involving vascular permeability, endothelial dysfunction, and chronic inflammation. However, evidence regarding the relationship between lipid abnormalities and macular edema remains inconsistent across s...

BackgroundRising kidney discard rates and uncertainty around accepting higher risk donor kidneys highlight the need for decision support tools that integrate donor and recipient factors and communicate risk in ways that are understandable and usable at the time of offer. Conventional indices (e.g., KDPI/KDRI) provide population level signals but do not deliver individualized, cognitively accessible information aligned with real time clinical workflows. ObjectiveTo describe how key transplant st...

Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface inte...

Tumour typing from whole-genome sequencing is increasingly accurate, yet molecular subtyping from somatic variants remains challenging because of tumour heterogeneity and inconsistent clinical annotations. Here, we present Mutation-Attention Dual-Task (MuAt2), a Transformer model that jointly classifies histological tumour types and subtypes directly from somatic single-nucleotide variants, indels and structural variants. MuAt2 leverages encoders pre-trained on 2,587 pan-cancer whole genomes, an...

Abstract Background: Enhanced Recovery After Surgery (ERAS) optimizes perioperative management for colorectal cancer (CRC), improving short-term outcomes, but its impact on long-term outcomes remains inconclusive, supporting the need for this meta-analysis. This study evaluates the effect of perioperative ERAS (therapy-focused) on 1-, 2-, 3-, and 5-year postoperative survival in patients with CRC. Methods: We conducted a systematic review and meta-analysis following a pre-registered protocol in ...

Study question: How is glycodelin, a glycoprotein secreted by reproductive tissues, causally related to reproductive diseases and traits? Summary answer: We present evidence for a causal role of sex hormones in determining glycodelin levels, but limited evidence that glycodelin subsequently causally impacts reproductive traits. What is known already: Glycodelin is expressed in female and male reproductive tissues and has four glycoforms (-A, -C, -F and -S), with the glycosylation pattern determi...

BackgroundHypertension affects over 30% of adults and is the leading risk factor for cardiovascular disease. It often presents without obvious symptoms, meaning that, although effective therapies exist, hypertension remains widely undiagnosed and insufficiently treated. Genomics-based prediction methods have shown only modest benefits for these disorders, but proteomic markers have demonstrated potential for greater predictive and clinical value. MethodsWe applied a novel machine-learning based...

Background and aims Iron deficiency (ID) and myocardial iron depletion (MID) are causally linked to heart failure (HF) in the general population and in preclinical models. ID is common amongst pregnant women, but its impact on cardiac adaptations to pregnancy is unknown. This study examines that impact, and its potential relevance to peripartum cardiomyopathy (PPCM). Methods. We provided female mice with iron-replete or iron-deficient diets, and monitored cardiac function and morphology longitud...

BackgroundThe relationship between hip osteoarthritis (hip OA) and Alzheimers disease (AD) presents a critical paradox within the emerging "bone-brain axis": widespread phenotypic comorbidity sharply contradicts evolutionary theories of biological antagonism. This study integrates longitudinal and multi-omic analyses to determine whether this clinical overlap masks an underlying genetic neuroprotection. MethodsWe analyzed longitudinal phenotypic data from 261,767 UK Biobank participants using C...

We report a previously undescribed genotypic configuration identified in twins with HNRNPU-related neurodevelopmental disorder. Both twins have two closely spaced mosaic variants on the same allele that never co-occur on any single DNA molecule, resulting in three distinct cell lineages within each individual. We define this genotypic configuration as clustered monoallelic mosaicism (cMoMa). Recognizing the extreme improbability of such a configuration, we systematically explore two potential me...

Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part o...

Background and ObjectivesAssociations of common infections with Alzheimer disease (AD) risk have been reported. A hypothesized mechanism to explain these is cerebral amyloid-beta (A{beta}) aggregation as a defence in response to infection, with subsequent tau accumulation. However, few studies have assessed associations of infections with tau and A{beta} pathology. We investigated associations of serological measures of several common infections with plasma p-tau217 and A{beta} status measured b...

Vaccination frequently elicits suboptimal immunogenicity in organ transplant recipients, particularly those on long-term immunosuppressive therapy, highlighting the need for improved understanding of immunosuppression mechanisms and optimized vaccination strategies. This study enrolled a cohort of 132 individuals and observed significantly lower antibody levels in kidney transplant recipients (KTRs) compared to non-transplant controls (non-KTRs). Antibody levels were inversely associated with bo...