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PubMed2026

Diagnosis and management of very rare primary arrhythmia syndromes in children and adults: a Clinical Consensus Statement of the European Heart Rhythm Association of the ESC and the Association of Cardiovascular Nursing & Allied Professions of the ESC, endorsed by the Association for European Paediatric and Congenital Cardiology.

Very rare and ultra-rare primary inherited arrhythmia syndromes (IAS) represent a heterogeneous group of disorders associated with a significant risk of sudden cardiac death, often manifesting from foetal life to early adulthood. Current guidelines primarily address more common IAS and provide limited, non-specific recommendations for these rare entities, particularly in paediatric populations. This European Heart Rhythm Association Clinical Consensus Statement, developed in collaboration with the Association of Cardiovascular Nursing and Allied Professions and endorsed by the Association for European Paediatric and Congenital Cardiology, integrates available evidence with expert opinion. Recommendations were formulated through structured discussion and voting, following ESC consensus methodology, with a focus on clinically actionable gene-disease associations. The document provides a comprehensive framework for the diagnosis and management of very rare IAS, including calmodulinopathies, Andersen-Tawil syndrome, Timothy syndrome, TRDN-related disease, calcium release deficiency syndrome, and other atypical channelopathies. It highlights age-specific clinical presentations, the importance of genetic testing, and tailored therapeutic strategies, including pharmacological treatments, left cardiac sympathetic denervation, and selective use of implantable cardioverter-defibrillators. Special attention is given to paediatric considerations, foetal diagnosis, and the role of multidisciplinary care. The document also addresses arrhythmic risk in metabolic and cardiomyopathic conditions, as well as the importance of molecular autopsy and family screening in sudden unexplained death. This consensus document fills a critical gap by providing expert-driven, pragmatic guidance for the management of very rare IAS across the lifespan. It underscores the need for specialized care, international collaboration, and prospective registries to improve evidence generation, risk stratification, and patient outcomes in this vulnerable population.

Humans↗

PubMed2026

Source- and Solubility-specific Choline, Gut Microbiota, and Dyslipidemia Risk: Trimethylamine N-oxide-associated and Non-trimethylamine N-oxide-Associated Patterns in a Prospective Cohort Study.

BACKGROUND: Dietary choline, a major precursor of the gut microbial metabolite trimethylamine N-oxide (TMAO), is implicated in dyslipidemia risk; however, source- and form-specific associations and interactions with gut microbiota remain unclear. OBJECTIVES: The aim of this study was to examine longitudinal associations of source- and form-specific dietary choline with plasma TMAO and dyslipidemia and to identify gut microbiota interactions. METHODS: Using data from the China Health and Nutrition Survey (2018-2023), dietary intake was assessed via 3 consecutive 24-h recalls in this prospective cohort study. Two-level generalized linear mixed-effects models were applied in 4828 adults (mean age: 55.9 ± 12.6 y, 56.6% females) to assess choline-dyslipidemia associations. Choline-TMAO and TMAO-dyslipidemia analyses were conducted in 1091 participants free of dyslipidemia at baseline. Among 7169 adults with gut microbiome data, Least Absolute Selection and Shrinkage Operator and logistic regression identified lipid-associated gut genera; TMAO relationships were examined in a subset of 693 participants. RESULTS: Higher intakes of total [Q4 compared with Q1: odds ratio (OR) = 1.261; 95% confidence interval (CI): 1.007, 1.580], red meat-derived (OR: 1.753; 95% CI: 1.196, 2.568), and lipid-soluble choline (OR: 1.304; 95% CI: 1.047, 1.624) were associated with higher risk of elevated low-density lipoprotein cholesterol (LDL cholesterol), whereas vegetable-derived choline was inversely associated. Egg-derived and lipid-soluble choline were positively associated with plasma TMAO, which was prospectively associated with 5-y incident dyslipidemia (Q4 compared with Q1-OR: 1.620; 95% CI: 1.047, 2.509), elevated LDL cholesterol (Q3 compared with Q1-OR: 2.478; 95% CI: 1.187, 5.174), and hypertriglyceridemia (Q4 compared with Q1-OR: 1.829; 95% CI: 1.028, 3.225). Three TMAO-associated genera were identified: Lachnospiraceae and Phascolarctobacterium as pro-risk taxa and Turicibacter as protective. The adverse LDLcholesterol association of egg-derived choline was observed exclusively in Phascolarctobacterium-enriched individuals. CONCLUSIONS: Dietary choline source and solubility differentially associated with dyslipidemia risk through TMAO-associated and non-TMAO-associated patterns, with gut microbiota as key modulators.

Humans↗

PubMed2026

Differential impacts of exon 1-associated and exon 11-associated variants of the rat mu opioid receptor gene, Oprm1, on buprenorphine- and morphine-induced analgesia and respiratory depression in male rats.

Buprenorphine has long been recognized as a mu opioid agonist with a distinctive and intricate pharmacological profile. It is a partial agonist at the mu opioid receptor, an antagonist at the kappa and delta opioid receptors, and an agonist at the nociception opioid receptor. Similar to other mu agonists such as morphine and fentanyl, buprenorphine can produce side effects, including tolerance, physical dependence, respiratory depression, and addiction. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, generating an array of splice variants or isoforms, which are conserved from rodents to humans. These splice variants can be categorized into 2 main types, exon 1 (E1)-associated variants and exon 11 (E11)-associated variants. E1-associated variants primarily consist of full-length, 7-transmembrane C-terminal variants, whereas E11-associated variants are typically truncated 6-transmembrane variants. Previous studies established that buprenorphine analgesia in mice is dependent on both E1- and E11-associated variants. However, the role of these variants in buprenorphine analgesia and respiratory depression in rats remains unclear. In this study, we used CRISPR/Cas9 technology to develop 2 rat Oprm1 gene-targeting models in which E1- and E11-associated variants were selectively disrupted, aiming to investigate their roles in buprenorphine and morphine's actions. The results showed that both E1- and E11-associated variants are essential for buprenorphine's analgesic and respiratory depressional effects in rats, whereas morphine's effects are solely attributed to the E1-associated variants. These findings provide new and important insights into the distinct contributions of the E1- and E11-associated variants to the pharmacological actions of buprenorphine and morphine. SIGNIFICANCE STATEMENT: Differential dependences of buprenorphine and morphine analgesia and respiratory depression on Oprm1 exon 1- and exon 11-associated variants revealed in rat gene-targeting models provide new and important insights into unique contributions of these variants to buprenorphine and morphine actions.

Animals↗

PubMed2025

Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukemia patients.

Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by poor survival outcomes. Further, due to the extreme molecular heterogeneity of the disease, drug treatment response varies from patient to patient. The variability of drug response can cause unnecessary treatment in more than half of the patients with no or partial therapy responses leading to severe side effects, monetary as well as time loss. Understanding the genetic risk factors underlying the drug response in AML can help with improved prediction of treatment responses and identification of biomarkers in addition to mechanistic insights to monitor treatment response. Here, we report the results of the first Exome-Wide Association Study (EWAS) of ex-vivo drug response performed to date with 175 AML cases and 47 drugs. We used information from 55,423 germline exonic SNPs to perform the analysis. We identified exome-wide significant (p < 9.02 × 10- 7) associations for rs113985677 in CCIN with tamoxifen response, rs115400838 in TRMT5 with idelalisib response, rs11878277 in HDGFL2 with entinostat, and rs2229092 in LTA associated with vorinostat response. Further, using multivariate genome-wide association analysis, we identified the association of rs11556165 in ATRAID, and rs11236938 in TSKU with the combined response of all 47 drugs and 29 nonchemotherapy drugs at the genome-wide significance level (p < 5 × 10- 8). Additionally, a significant association of rs35704242 in NIBAN1 was associated with the combined response for nonchemotherapy medicines (p = 2.51 × 10- 8), and BI.2536, gefitinib, and belinostat were identified as the central traits. Our study represents the first EWAS to date on ex-vivo drug response in AML and reports 7 new associated loci that help to understand the anticancer drug response in AML patients.

Humans↗

PubMed2026

High-Density Genome-Wide Association Mapping Identifies Candidate Loci Associated with Maize Stalk Cell Wall Composition.

Maize (Zea mays L.) stalk cell wall composition is a key determinant of forage digestibility, lodging resistance, and biomass utilization efficiency. Although previous genome-wide association studies (GWAS) have identified loci associated with lignin (LIG), cellulose (CEL), and hemicellulose (HC), advances in genomic resources provide an opportunity to revisit existing phenotypic datasets at substantially higher resolution. Here, we re-analyzed a maize association panel consisting of 341 diverse inbred lines using an expanded genotype dataset containing 10.77 million SNPs, two derived compositional indices (CEL/HC and [LIG/(CEL + HC)], and six complementary GWAS models. Across all traits and models, we identified 855 unique significant SNPs associated with 579 candidate genes. Among the traits examined, LIG/(CEL + HC) yielded the greatest number of associations, suggesting that indices representing the relative balance among cell wall components may better capture the genetic architecture of cell wall composition than individual component measurements alone. Integration of multiple GWAS models with functional enrichment, haplotype, and selective sweep analyses prioritized three biologically relevant candidate genes encoding a MYB58 transcription factor, the glycosyltransferase Xt9, and a putative xyloglucan 6-xylosyltransferase. Haplotype analysis revealed significant effects of Xt9 and the xyloglucan 6-xylosyltransferase on cell wall composition, while selective sweep analysis identified Xt9 as a target of repeated selection during maize domestication, ecological adaptation, and modern breeding. Although these candidate genes provide promising targets for future investigation, the associations identified here are based on a single association panel and require functional and independent population validation. Collectively, our results demonstrate how high-density genotyping combined with complementary GWAS models can refine candidate associations and generate testable hypotheses from existing phenotypic datasets.

cell wall composition↗

PubMed2026

FMT alleviates multidrug-resistant Salmonella enterica-induced diarrhea and is associated with loss of IncHI2A-associated resistance determinants in mice.

INTRODUCTION: Multidrug-resistant (MDR) Salmonella enterica (S. enterica) poses a serious threat to animal and public health because of increasingly limited treatment options. Fecal microbiota transplantation (FMT) is a potential microbiota-based intervention; however, its effects on MDR Salmonella infection and pathogen-associated antibiotic resistance gene (ARG) dynamics remain unclear. METHODS: A murine diarrhea model was established using the clinical MDR S. enterica isolate P174, and infected mice were treated with FMT. Clinical symptoms, intestinal pathology, transcriptional inflammatory responses, gut microbiota composition, and ARG profiles of recovered Salmonella isolates were evaluated. Whole-genome sequencing was used to characterize resistance determinants, and the stability of ARGs and IncHI2A backbone markers was further assessed during 19 in vitro passages. RESULTS: FMT reduced diarrhea, promoted body weight recovery, and alleviated intestinal tissue injury and inflammatory cell infiltration. Colonic expression of Tnf, Il1b, and Il6 decreased, whereas Il10 expression increased. FMT was also associated with partial recovery of gut microbial diversity, increased relative abundances of Lactobacillus, Bifidobacterium, and other commensal anaerobic taxa, and reduced Salmonella abundance. Whole-genome sequencing showed that bla OXA-1, floR, oqxA, and oqxB were co-localized on an IncHI2A-associated plasmid sequence. Loss of these resistance determinants increased over time in isolates recovered from FMT-treated mice, whereas no loss of the four ARGs or the IncHI2A backbone markers repB and parB was detected during 19 in vitro passages. Among isolates showing simultaneous loss of all four ARGs, nearly all also lacked detectable repB and parB, whereas isolates with partial ARG loss retained both markers. These patterns were consistent with both backbone-associated loss and resistance-region deletion or rearrangement. Most ARG-loss isolates showed reduced antimicrobial resistance. DISCUSSION: FMT alleviated MDR S. enterica-induced intestinal disease and was associated with partial recovery of gut microbiota characteristics and increased instability and loss of IncHI2A-associated resistance determinants in vivo. These findings suggest a potential association between intestinal microbial ecological changes and altered maintenance patterns of resistance-associated genetic elements in MDR S. enterica.

Salmonella enterica↗

PubMed2025

Genome wide association study reveals novel associations with face morphology.

Genome-wide association studies (GWAS) on the Middle Eastern population, including the United Arab Emirates (UAE), have been relatively limited. The present study aims to investigate genotype-face morphology associations in the UAE population through Genome Wide Association Studies (GWAS). Phenotypic data (44 face measurements) from 172 Emiratis was obtained through three-dimensional (3D) scanning technology and an automatic face landmarking technique. GWAS analysis revealed associations of 19 genetic loci with six face features, 14 of which are novel. The GWAS analysis revealed 11 significant relationships between 44 face parameters and 242 SNPs, exceeding the GWAS significance threshold. These phenotypes were previously associated with body height, craniofacial defects, and facial characters. The most significant associations of these genetic variations were related to six main facial features which were facial convexity, left orbital protrusion, mandibular contour, nasolabial angle D, inferior facial angle B, and inferior facial angle A. To the best of our knowledge, this is the first GWAS study to investigate the association of SNP variations with face morphology in the Middle Eastern population.

Humans↗

PubMed2024

Virulence-associated variants in Cryptococcus neoformans sequence type 93 are less likely to be associated with population structure compared to independent rare mutations.

Cryptococcus neoformans is a pathogenic yeast that is the causative agent of cryptococcal meningitis. While it is well known that the genotype of C. neoformans impacts patient outcomes, the reason for this association has not been well elucidated. In this study, we examined the relationship between two subpopulations in the sequence type 93 clade of C. neoformans: ST93A and ST93B. We found extensive linkage disequilibrium (LD) among the single nucleotide polymorphisms (SNPs) that differentiate ST93A from ST93B. We also found differences in the extent of linkage among SNPs within each subpopulation; LD was more extensive within ST93B than ST93A. SNPs associated with virulence were in long-range linkage disequilibrium with less frequency than recurrent SNPs not associated with virulence. We investigated the karyotype of ST93A and ST93B using contour-clamped gel electrophoresis and long-read sequencing and found that the extensive long-range linkage was not due to chromosomal rearrangements. Overall, we found that the two subpopulations in ST93 are driven by SNPs in LD. We additionally found that recurrent SNPs associated with virulence were less frequently evolutionarily linked and were two times more likely to be independent, congruent mutations rather than tied to phylogeny.IMPORTANCECryptococcus neoformans is an important pathogen that is widely distributed and ubiquitous in the environment. The majority of the human population has a latent, controlled infection suggesting that C. neoformans is uniquely adapted to cause infection. In spite of this, the reason C. neoformans is a pathogen remains unknown; interestingly, most environmental isolates are avirulent but are genetically very similar to disease-causing virulent isolates. Recent evidence from genome-wide association studies shows that small mutations in key virulence-associated genes are associated with the virulence of specific isolates. The data presented here provide an evolutionary framework for those small mutations. The mutations that impact disease are not being collected over long-term evolution. The mutations may instead occur independently during infection. Identifying these genes that are more likely to be mutated during infection will be fundamental for understanding C. neoformans virulence.

Cryptococcus neoformans↗

PubMed2026

A STORM-based protocol for nanoscale imaging and quantitative analysis of protein-associated and phospholipid-associated structures in natural rubber.

Stochastic Optical Reconstruction Microscopy (STORM) enables nanoscale mapping of molecular components beyond the diffraction limit; however, its reproducible implementation in hydrophobic polymer matrices remains challenging because fluorescence-labeling specificity, fluorophore photoswitching, three-dimensional localization, chromatic registration, and quantitative image analysis must be carefully controlled. This protocol presents a standardized experimental workflow for dual-color labeling, astigmatism-based three-dimensional STORM acquisition, and quantitative analysis of protein-associated and phospholipid-associated structures in natural rubber (NR). The workflow covers sample pretreatment, Cy5 NHS ester labeling of protein-associated primary amines, DiI labeling of phospholipid-rich domains, STORM imaging-buffer preparation, three-dimensional single-molecule localization, dual-channel registration, generation of standardized xy projections, aggregate-size analysis, and projected lateral spatial correlation assessment. Reproducibility is supported by defined acquisition and localization criteria, three independent sample preparations with at least five fields of view analyzed per condition, and unlabeled, single-color, dye-only matrix, and processing-associated Cy5 controls. Mean lateral localization precisions of 11.8 ± 2.3 nm for Cy5 and 13.5 ± 2.9 nm for DiI were obtained, while two-dimensional Fourier ring correlation analysis of the xy projections yielded effective lateral image resolutions of approximately 25 and 28 nm, respectively. Image-based particle segmentation and localization-coordinate-based density-based spatial clustering of applications with noise (DBSCAN) were applied to standardized xy projections as complementary quantitative approaches. Application of the protocol to untreated, centrifuged, and protease-treated NR samples demonstrated treatment-associated changes in the detected abundance and projected size distributions of protein- and phospholipid-associated aggregates, together with a non-monotonic change in their projected lateral spatial correlation. These observations describe alterations in nanoscale organization but do not, by themselves, establish stable protein-phospholipid complex formation. Unlike previous studies that primarily demonstrated the feasibility of STORM imaging in rubber materials, the principal contribution of this work is an end-to-end, step-by-step protocol incorporating defined controls, three-dimensional localization, image-quality metrics, chromatic-registration procedures, and complementary quantitative-analysis pipelines for non-expert users. The workflow may be adaptable to other hydrophobic polymers and soft-material systems after appropriate optimization and validation.

Rubber↗

PubMed2026

Tumor-associated macrophages display differential protein cargo sorting in extracellular vesicles associated with poor survival in ovarian cancer.

Ovarian cancer (OC) progression and metastasis are promoted by ascites, which constitutes a central part of the tumor microenvironment (TME). In this fluid, tumor-associated macrophages (TAMs) represent a prominent immune cell type. In addition to tumor and other host cells such as TAMs, ascites is highly enriched in soluble factors as well as extracellular vesicles (EVs). How TAMs contribute to the EV compartment of the OC TME remains, however, underexplored. In this work peripheral blood monocytes from healthy donors were differentiated into monocyte-derived macrophages (MDMs) and polarized into classically activated (M1-like), alternatively activated (M2-like) and TAM-like (by ascites incubation). For all subtypes, serum-free conditioned medium was collected for 24 h and EVs were isolated and characterized by nano-flow cytometry (nFC), label-free mass spectrometry-based proteomics and electron microscopy, among others. Our results demonstrated distinct traits for EV release and cargo across the different macrophage subtypes. Specifically, TAM-like macrophages exhibited impaired release of small EVs and reduced frequency of tetraspanin-positive particles. These EV subpopulations displayed sizing profiles closer to M1-like than to M2-like samples. Also, the low EV release in TAM-like MDMs was accompanied by altered expression of biogenesis-related markers like flotillin-1 (FLOT1) and a decreased N-glycosylation of CD63 protein, which was validated in patient-derived samples. Remarkably, the EV-associated proteome of TAMs displayed significant enrichment in both pro- and anti-inflammatory molecules with clinical value. Markers significantly enriched in the ascites TAM-EV signature were mostly associated with poor prognosis, whereas M1-like EV-related markers (pro-inflammatory) were mostly associated with longer survival. Our results confirmed previous data for proteins like CD163 and MRC1 to be associated to TAM-EVs, while also describing novel candidates with diagnostic (i.e., COLEC12) and/or prognostic (i.e., MSR1) value in plasma. Taken together, our data support a unique secretory profile of TAMs in OC and provide new EV-associated biomarkers with translational impact. Our results pave the way for a better understanding of the mechanisms behind TAM-EV cargo loading and function, and how these cells participate in the TME landscape.

Humans↗

PubMed2026

Long-term seizure outcomes and factors associated with response to adjunctive everolimus in TSC-associated epilepsy.

BACKGROUND: Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, is increasingly used in tuberous sclerosis complex (TSC)-associated epilepsy; however, long-term real-world outcomes and factors associated with favorable response remain unclear. This study aimed to evaluate the long-term seizure outcomes of adjunctive everolimus and explore clinical factors associated with treatment response. METHODS: We retrospectively recruited 21 patients with active TSC-associated epilepsy receiving adjunctive everolimus and assessed seizure outcomes during follow-up. Clinical characteristics were compared between responders and non-responders at 1 year after treatment initiation. RESULTS: Over a median treatment duration of 72 months, responder rates ranged from 53.8% to 64.7%, and seizure-free rates ranged from 33.3% to 41.2%. Responders had fewer involved organ systems at baseline (median 3 vs. 4, p = 0.020) and lower anti-seizure medication burden (median 2 vs. 4, p = 0.045). Younger age at treatment initiation showed a trend toward improved response. CONCLUSION: Adjunctive everolimus was associated with sustained long-term seizure reduction in this real-world cohort. In exploratory analyses, fewer involved organ systems and fewer baseline ASMs were associated with favorable treatment response. These findings require validation in larger prospective cohorts.

Epilepsy↗

PubMed2025

Genome-wide association study of angiotensinogen levels and key single nucleotide polymorphism associations with blood pressure.

OBJECTIVE: The renin angiotensin aldosterone system plays a key role in circulatory homeostasis. We sought to identify genetic determinants of measured plasma angiotensinogen levels and subsequently evaluate the association of these single nucleotide polymorphisms (SNPs) with blood pressure (BP) and hypertension in a multiethnic population. METHODS: Genome-wide association study (GWAS) of plasma angiotensinogen levels, measured using an enzyme-linked immunoassay, was conducted in 4899 Multi-Ethnic Study of Atherosclerosis (MESA) participants (self-identified as White, n = 1865; Hispanic, n  = 1113; Black, n  = 1224; and Chinese, n  = 629). Linear and logistic models examined the association between SNPs with angiotensinogen and hypertension, respectively. Mediation analysis evaluated the effect of angiotensinogen on BP/hypertension through the top SNPs identified by GWAS. RESULTS: In the analysis utilizing all participants, 115 SNPs were associated with angiotensinogen ( P  < 5 × 10 -8 ), including lead SNP rs4762(G>A) in exon 2 ( P  = 1.51E -100 ) and rs5050(T>G) in the promoter region ( P  = 2.26E -69 ) of the AGT gene. Race/ethnic-specific analyses identified rs4762(G>A) as the lead SNP for White and Hispanic participants, whereas Black and Chinese participants had rs5050(T>G) and rs16852311(G>C), respectively. Both rs4762(G>A) and rs5050(T>G) indirectly increased systolic BP, diastolic BP, and the odds of hypertension through its effect of increasing angiotensinogen. CONCLUSIONS: Our findings demonstrate racial/ethnic differences in genetic effects on angiotensinogen levels across multiple SNPs. AGT rs4762(G>A) and rs5050(T>G) impact BP and hypertension through a mediated effect via angiotensinogen, though opposing direct effects may mask the overall association.

Humans↗

PubMed2026

The association between GLP-1R expression and cardiovascular-kidney-metabolic-related diseases in non-diabetic and non-obese population: evidence triangulation using Mendelian randomization, observational and polygenic score association analysis.

BACKGROUND: Glucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank. RESULTS: GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10- 10 ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10- 8) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10- 3) in the general population. Consistent results were observed in validation analyses. Furthermore, PGS and observational analyses among non-T2DM and non-obese individuals found little evidence to support its association with CKD, HF or MASLD. GWAS analysis identified eight conditionally independent variants associated with MASLD, in which rs563199662 was a new signal located at TFPI region. CONCLUSIONS: This study provides multilayered evidence for GLP-1R expression in mitigating CKD, HF and MASLD risks in the general population, while de-prioritized its effect on CKM-related diseases in non-obese and non-diabetic individuals. Further clinical trials are needed to validate the effects of GLP-1R agonists in relative health population.

Humans↗

PubMed2026

Genome-wide association study reveals two novel genetic loci associated with chronic lung allograft dysfunction.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) leads to declining respiratory function and high mortality, representing the main barrier to long-term survival in lung transplantation (LT). We performed the first genome-wide association study (GWAS) investigating donor's and recipient's genetic factors associated with CLAD. METHOD: We genotyped 392 donor-recipient pairs from the multicentric Cohort in Lung Transplantation. We tested 4.5 million SNPs for association with CLAD using multivariable logistic regression models corrected for age, sex, initial disease and genetic ancestry. Three levels of explanatory variables were separately considered to conduct GWAS: donors-only, recipients-only, and donor-recipient mismatches. We also ran HLA-centric analyses using the same models. RESULTS: Our analysis confirmed the deleterious impact of HLA allelic and epitopic mismatches on CLAD risk, mostly driven by class I HLA (p=0.004). No significant associations with CLAD were found for donors' genotypes or donor-recipient non-HLA mismatches. We highlighted two independent recipient's loci associated with CLAD, including one protective signal (0.39 in CLAD vs 0.66 in non-CLAD recipients, p-value=5.05×10-7, q-value=0.017, OR=0.35) encompassing the PLXDC2 gene, and one risk signal (0.66 in CLAD vs 0.38 in non-CLAD recipients, p-value=9.86×10-7, q-value=0.017, OR=2.83) encompassing the ZNF518A/BLNK genes. These non-coding SNPs are putative regulatory variants of gene expression. Importantly, our single-cell RNA-sequencing showed a down-regulation of PLXDC2 in fibroblasts and lung epithelium in CLAD vs healthy controls. CONCLUSION: This first LT GWAS revealed two candidate loci from the recipient's genome, both biologically relevant for CLAD pathogenesis. Our study calls for larger LT genomic initiatives to increase power for signal discovery.

Humans↗

PubMed2026

Suggestive genome-wide associations with inflammatory biomarkers in an admixed population, including a missense variant in the OR6K6 olfactory receptor gene associated with MCP-1.

BACKGROUND: Chronic low-grade inflammation drives cardiometabolic diseases and has a strong genetic basis. Most genome-wide association studies (GWAS) have focused on European populations, limiting knowledge of the genetic influences on inflammation in admixed populations such as those in Brazil. METHODS: This study is part of the cross-sectional ISA Capital Health Survey. It uses data from the 2015 ISA Nutrition cohort, which measured biochemical, genetic, anthropometric, and lifestyle factors in a probabilistic sample of São Paulo residents. Genomic DNA was extracted from 841 individuals. Genotyping was performed using the Axiom 2.0 Precision Medicine Research Array. After quality control and missing data exclusion, 244,338 SNPs from 638 individuals remained for GWAS-based association analysis with eight inflammatory biomarkers. Models were adjusted for sex, age, age2, overweight, and the first two principal components of ancestry. RESULTS: Most participants were male (53%) and not overweight (55%). The median age was 49, and 38% were older adults. In the genome-wide analysis of TNF-α, IL-10, IL-1β, monocyte chemoattractant protein-1 (MCP-1), and adiponectin, 12 SNPs were significantly associated, most of which were intronic. Notably, one signal mapped to the missense variant rs16841009 in the olfactory receptor gene OR6K6. This variant was associated with MCP-1, suggesting a possible involvement in inflammatory responses. CONCLUSIONS: We identified new SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population, including a missense variant in an olfactory receptor gene linked to MCP-1. This association may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.

Humans↗

PubMed2026

Metabolic Dysfunction-Associated Steatotic Liver Disease Is Associated With Adverse Social Factors: An Analysis Using All of Us.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is progressive, with estimated global prevalence exceeding 30%. Social determinants of health (SDOH) may impact MASLD risk and progression. However, this has not been fully characterized. We harnessed the power of the All of Us Research Program (AoU) dataset to conduct a comprehensive analysis examining the association between various SDOH and MASLD. METHODS: We conducted a retrospective cross-sectional analysis of the AoU database. We identified participants with MASLD using ICD-9 and -10 codes and excluded individuals with other chronic liver diseases or self-reported heavy alcohol use. Healthy control participants were devoid of chronic liver diseases, heavy alcohol use, and comorbidities associated with MASLD if obese. We examined SDOH by combining relevant questions from various AoU surveys and conducted univariate and multivariate logistic regression to examine the association between various SDOH and MASLD. RESULTS: After matching cases to controls by age and race/ethnicity, the sample of 57,895 participants had a 1:3 case to control ratio; 16,666 had complete SDOH survey data (MASLD to controls, 1:3.4). Compared to controls, individuals with MASLD were more likely to have less than a high school education (10.7% vs 9.7%; P < .001) and annual income ≤$35,000 (42.4% vs 34.3%; P < .001). Compared to controls, participants with MASLD had significantly higher levels of social isolation, neighborhood disorder, perceived stress, food insecurity, and transportation insecurity (P < .001 for all). CONCLUSION: The study identified significant associations between MASLD and multiple SDOH. Future studies should investigate how SDOH interact to drive MASLD risk and progression.

All of Us↗

PubMed2026

Membrane-associated compartmentalization of zearalenone biosynthetic enzymes and Syn2-associated zearalenone homeostasis in Fusarium graminearum.

Subcellular compartmentalization has attracted increasing attention in fungal secondary metabolism, particularly in the biosynthesis and trafficking of mycotoxins. However, the subcellular site of zearalenone (ZEA) biosynthesis and the mechanisms underlying its export in Fusarium graminearum remain poorly understood. ZEA is a polyketide mycotoxin that poses a serious threat to food safety through contamination of cereal grains and induces severe estrogenic effects in mammals. Its biosynthesis is governed by a dedicated biosynthetic gene cluster consisting of PKS4, PKS13, ZEB1, and ZEB2. In this study, we investigated the subcellular organization of the ZEA biosynthetic machinery and found that key biosynthetic enzymes accumulated in punctate structures that overlapped with small CMAC-positive vacuolar structures and were closely associated with FM4-64-labeled membranes. Furthermore, our results suggest that the syntaxin-like t-SNARE protein Syn2 contributes to extracellular ZEA accumulation and intracellular toxin homeostasis. Disruption of SYN2 abolished visible ZEA crystal formation on the hyphal surface and was associated with increased intracellular ZEA retention. This intracellular accumulation was accompanied by strong induction of the ZEA biosynthetic gene cluster and reduced cellular viability. Moreover, deletion of ZEB2 in the Δsyn2 background abolished ZEA production and restored cell viability, supporting an association between Zeb2-dependent ZEA biosynthesis and the cytotoxic phenotype of the Δsyn2 mutant. Together, our findings suggest a potential link between membrane-associated organization of ZEA biosynthetic enzymes, Syn2-associated ZEA distribution, intracellular toxin homeostasis, and fungal viability. Further studies will be required to define the precise mechanisms underlying ZEA transport and compartment function.

Fusarium graminearum↗

PubMed2025

FAM13A polymorphism is associated with a usual interstitial pneumonia pattern in patients with systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: The MUC5B promoter single nucleotide polymorphism (SNP) rs35705950 has been associated with idiopathic pulmonary fibrosis (IPF) and RA-related interstitial lung disease (ILD), but not with SSc-ILD. We hypothesized that the MUC5B promoter polymorphism or other IPF susceptibility loci are associated with an increased risk for the uncommon SSc-usual interstitial pneumonia (UIP) endophenotype, rather than SSc-ILD in general. METHODS: We performed a cross-sectional study of SSc-ILD patients from four US Scleroderma Programs to investigate the frequency of MUC5B rs35705950 and 12 additional IPF susceptibility loci. SSc-ILD patients were stratified by high resolution chest CT (HRCT) imaging findings into UIP and non-UIP groups. Analysis of HRCTs performed by a thoracic radiologist blinded to participants' characteristics classified each scan as definite UIP, probable UIP, indeterminate or alternative diagnosis, according to American Thoracic Society criteria. RESULTS: Four-hundred and eighty-nine SSc-ILD patients were included; 80% were female and 75% were White. Twenty-three (4.7%) patients had a definite UIP pattern. The MUC5B SNP rs35705950 was not associated with a definite UIP pattern in SSc-ILD. In contrast, patients carrying two copies of the IPF risk gene FAM13A minor allele rs2609255 had significantly higher odds of a definite UIP pattern compared with the other patterns (odds ratio 3.40, 95% CI 1.19-9.70), and compared with an alternative diagnosis (odds ratio 3.65, 95% CI 1.25-10.65). CONCLUSION: We demonstrated a novel association between FAM13A and SSc-UIP. Contrary to IPF and RA-ILD, the MUC5B promoter polymorphism was not associated with a definite UIP pattern in SSc-ILD.

Humans↗