Intrahepatic levels of microbiome-derived hippurate associates with improved metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player of liver metabolism and health through the production of bioactive compounds that are beneficial for its host - "postbiotics". Circulating hippurate, a host-microbial co-metabolite produced by conjugating microbial benzoate with glycine in the host-liver, is associated with human gut microbial gene richness and with metabolic health.

A framework for conducting GWAS using repeated measures data with an application to childhood BMI.

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in GWAS. Using childhood BMI as an example trait, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound.

Obesity: exploring its connection to brain function through genetic and genomic perspectives.

Obesity represents an escalating global health burden with profound medical and economic impacts. The conventional perspective on obesity revolves around its classification as a "pure" metabolic disorder, marked by an imbalance between calorie consumption and energy expenditure. Present knowledge, however, recognizes the intricate interaction of rare or frequent genetic factors that favor the development of obesity, together with the emergence of neurodevelopmental and mental abnormalities, phenotypes that are modulated by environmental factors such as lifestyle.

PNLIPRP1 Hypermethylation in Exocrine Pancreas Links Type 2 Diabetes and Cholesterol Metabolism.

We postulated that type 2 diabetes (T2D) predisposes patients to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (using MethylationEPIC arrays) of the exocrine pancreas in 141 donors, assessing the impact of T2D. An epigenome-wide association study of T2D identified hypermethylation in an enhancer of the pancreatic lipase-related protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression.

Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function.

Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes.

Towards the recognition of oligogenic forms of type 2 diabetes.

The demarcation between monogenic and polygenic type 2 diabetes (T2D) is less distinct than previously believed. Notably, recent research has highlighted a new entity, that we suggest calling oligogenic forms of T2D, serving as a genetic link between these two forms. In this opinion article, we have reviewed scientific advances that suggest categorizing genes involved in oligogenic T2D.

comorbidPGS: An R Package Assessing Shared Predisposition between Phenotypes Using Polygenic Scores.

Introduction: Polygenic score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While polygenic risk scores are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e.

Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function.

Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers.

A framework for conducting time-varying genome-wide association studies: An application to body mass index across childhood in six multiethnic cohorts.

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound.

Pathogenic, Total Loss-of-Function DYRK1B Variants Cause Monogenic Obesity Associated With Type 2 Diabetes.

Objective: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated.

Research Design And Methods: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes.

Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.

Objective: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D).

Methods: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D.

Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD.

Background & Aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers.

Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas.

Aims/hypothesis: GLIS3 encodes a transcription factor involved in pancreatic beta cell development and function. Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk. Because rare, functional variants located in other susceptibility genes for type 2 diabetes have already been shown to strongly increase individual risk for common type 2 diabetes, we aimed to investigate the contribution of rare pathogenic GLIS3 variants to type 2 diabetes.

Genetic variants of interferon-response factor 5 are associated with the incidence of chronic kidney disease: the D.E.S.I.R. study.

Inflammation has been associated with renal diseases. The Interferon Regulatory Factor (IRF)-5 is a key transcription factor in the pro-inflammatory polarization of M1-like macrophages. GWAS have reported that the IRF5 locus is associated with autoimmune diseases and with the estimated glomerular filtration rate (eGFR).

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide.

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles.

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals.

High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor.

The long-term clinical outcomes of severe obesity due to leptin signaling deficiency are unknown. We carry out a retrospective cross-sectional investigation of a large cohort of children with leptin (LEP), LEP receptor (LEPR), or melanocortin 4 receptor (MC4R) deficiency (n = 145) to evaluate the progression of the disease. The affected individuals undergo physical, clinical, and metabolic evaluations.

Identification of myokines susceptible to improve glucose homeostasis after bariatric surgery.

Importance And Objective: The identification of myokines susceptible to improve glucose homeostasis following bariatric surgery could lead to new therapeutic approaches for type 2 diabetes.

Methods: Changes in the homeostasis model assessment (HOMA) test were assessed in patients before and 3 months after bariatric surgery. Changes in myokines expression and circulating levels were assessed using real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA).