Genetic Evidence Research Articles

Genetic Evidence for GLP-1 and GIP Receptors as Targets for Treatment and Prevention of MASLD/MASH.

Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty. We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP-1/GIP concentrations and MASLD and its related traits. Next, we conducted drug-target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD-related traits. Circulating 2-h GLP-1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (ORGLP-1 = 0.168 [95% CI 0.033-0.839], p = 0.030; ORGIP = 0.331 [95% CI 0.222-0.494], p = 6.31 × 10-8). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531-0.849], p = 9.07 × 10-4). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD-related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index. GLP-1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement.

MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss.

Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1-knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1-knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans.

Causal association between insulin sensitivity index and Alzheimer's disease.

Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post-prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome-wide significant (p < 5E-08, primary analyses) and 61 suggestive (p < 1E-05, secondary analyses) ISI genetic variants from large-scale genome-wide association studies (GWAS; N = 53 657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (N = 63 926) and FinnGen_G6_AD_WIDE (N = 412 181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta-analysis to combine MR estimates from two non-overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR = 0.79, 95% CI: 0.68-0.92, p = 0.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR = 0.89, 95% CI: 0.82-0.96, p = 0.003). Heterogeneity, horizontal pleiotropy test, and leave-one-out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (p > 0.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR-associated T2D and AD.

Nifuroxazide rescues the deleterious effects due to CHCHD10-associated MICOS defects in disease models.

The identification of a point mutation (p.Ser59Leu) in the CHCHD10 gene was the first genetic evidence that mitochondrial dysfunction can trigger motor neuron disease. Since then, we have shown that this mutation leads to the disorganization of the MItochondrial contact site and Cristae Organizing System (MICOS) complex that maintains the mitochondrial cristae structure. Here, we generated yeast mutant strains mimicking MICOS instability and used them to test the ability of more than 1600 compounds from 2 repurposed libraries to rescue the growth defect of those cells. Among the hits identified, we selected nifuroxazide, a broad-spectrum antibacterial molecule. We show that nifuroxazide rescues mitochondrial network fragmentation and cristae abnormalities in CHCHD10S59L/+ patient fibroblasts. This molecule also decreases caspase-dependent death of human CHCHD10S59L/+ iPSC-derived motor neurons. Its benefits involve KIF5B-mediated mitochondrial transport enhancement, evidenced by increased axonal movement and syntaphilin degradation in patient-derived motor neurons. Our findings strengthen the MICOS-mitochondrial transport connection. Nifuroxazide and analogues emerge as potential therapeutics for MICOS-related disorders like motor neuron disease. Its impact on syntaphilin hints at broader neurological disorder applicability for nifuroxazide.

The MON1-CCZ1 complex plays dual roles in autophagic degradation and vacuolar protein transport in rice.

Autophagy is a highly conserved cellular program in eukaryotic cells which mediates the degradation of cytoplasmic components through the lysosome, also named the vacuole in plants. However, the molecular mechanisms underlying the fusion of autophagosomes with the vacuole remain unclear. Here, we report the functional characterization of a rice (Oryza sativa) mutant with defects in storage protein transport in endosperm cells and accumulation of numerous autophagosomes in root cells. Cytological and immunocytochemical experiments showed that this mutant exhibits a defect in the fusion between autophagosomes and vacuoles. The mutant harbors a loss-of-function mutation in the rice homolog of Arabidopsis thaliana MONENSIN SENSITIVITY1 (MON1). Biochemical and genetic evidence revealed a synergistic interaction between rice MON1 and AUTOPHAGY-RELATED 8a in maintaining normal growth and development. In addition, the rice mon1 mutant disrupted storage protein sorting to protein storage vacuoles. Furthermore, quantitative proteomics verified that the loss of MON1 function influenced diverse biological pathways including autophagy and vacuolar transport, thus decreasing the transport of autophagic and vacuolar cargoes to vacuoles. Together, our findings establish a molecular link between autophagy and vacuolar protein transport, and offer insights into the dual functions of the MON1-CCZ1 (CAFFEINE ZINC SENSITIVITY1) complex in plants.

No genetic causality between appendectomy and gastrointestinal cancers: a Mendelian randomization study and meta-analysis in European population

The impact of appendectomy on the risk of gastrointestinal cancers remains unknown. We aimed to systematically estimate the causal relationship between appendectomy and gastrointestinal cancers in the European population using two-sample Mendelian randomization (TSMR) study methods and meta-analysis. As part of the discovery cohort analysis, we identified independent genetic variants strongly associated with appendectomy from the UK Biobank (50,105 cases) to serve as instrumental variables (IVs). Summary-level data for gastrointestinal cancers were obtained from the FinnGen study. As the replication cohort, IVs associated with appendectomy were extracted in the FinnGen study (28,601 cases). The data for gastrointestinal cancers were obtained from the UK Biobank. Finally, meta-analyses were conducted to evaluate the combined causal effects of the MR results. We found no causal relationship between appendectomy and gastrointestinal cancers in both the discovery and replication cohorts. Finally, the meta-analysis revealed no causal association between appendectomy and gastrointestinal cancers. Our findings suggest no causal relationship exists between appendectomy and gastrointestinal cancers in the European population. This genetic evidence supports the conclusion from other observational studies that appendectomy does not affect the risk of gastrointestinal cancers in the European population.

Transcriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-related drug targets for cardiometabolic diseases

Immunity has shown potentials in informing drug development for cardiometabolic diseases, such as type 2 diabetes (T2D) and coronary artery disease (CAD). Here, we performed a transcriptome-wide Mendelian randomization (MR) study to estimate the putative causal effects of 11,021 gene expression profiles during CD4+ T cells activation on the development of T2D and CAD. Robust MR and colocalization evidence was observed for 162 genes altering T2D risk and 80 genes altering CAD risk, with 12% and 16% respectively demonstrating CD4+ T cell specificity. We observed temporal causal patterns during T cell activation in 69 gene-T2D pairs and 34 gene-CAD pairs. These genes were eight times more likely to show robust genetic evidence. We further identified 25 genes that were targets for drugs under clinical investigation, including LIPA and GCK. This study provides evidence to support immune-to-metabolic disease connections, and prioritises immune-mediated drug targets for cardiometabolic diseases.

Type 2 diabetes prevention: genetic association analysis of dried fruit intake and disease risk.

Prior research has suggested an inverse correlation between dried fruit intake and type 2 diabetes mellitus (T2DM), yet the causal link remains uncertain. This study seeks to investigate the potential causal impact of dried fruit intake on T2DM, covering cases both with and without various complications, as well as glycaemic traits, using a two-sample Mendelian randomisation (MR) approach. Using MR analysis with genome-wide association study summary statistics, the primary analysis investigated the causal relationship between dried fruit intake and T2DM, both with and without complications, as well as glycaemic traits, employing the inverse variance weighted method. Supplementary analyses were conducted using MR-Egger and the weighted median method. Heterogeneity and intercept tests were utilised to evaluate the robustness of the study outcomes. The results show a significant association between dried fruit intake and T2DM without complications, as well as fasting insulin. Sensitivity analyses confirmed the robustness of the results and the independence from multicollinearity. However, no association was found between dried fruit intake and T2DM with various complications or other glycaemic traits. The significant association between dried fruit intake and T2DM without complications and fasting insulin persisted even after adjusting for BMI. This study offers genetic evidence endorsing the protective effects of dried fruit intake against T2DM, specifically for cases without complications, and in regulating fasting insulin. These findings suggest that dried fruit intake might serve as a primary preventive strategy for T2DM.

Deciphering lipoprotein(a) atherogenicity with use of high-throughput proteomics

Abstract Background Accumulating observational and genetic evidence suggests that lipoprotein(a) [Lp(a)], is significantly more atherogenic than other apolipoprotein-B containing particles. Systemic inflammation is thought to mediate the atherogenic effects of Lp(a). Previous studies have predominantly focused on single inflammatory biomarkers, an approach that fails to capture the broader molecular response to elevated Lp(a) levels. Purpose The aim of this study was to derive a proteome-wide signature of plasma Lp(a) concentrations and subsequently identify the pathways through which Lp(a) influences the risk of coronary artery disease (CAD). Methods This study included 41,123 UK Biobank participants with baseline Lp(a) measurements who also underwent a proteomic assessment. Relative concentration of 2,920 proteins was quantified in EDTA plasma samples using a high-throughput proximity extension assay. Lp(a)-associated proteins were identified in linear regression models, adjusting for age, sex, body mass index, race, smoking status, estimated glomerular filtration rate, medication use, and apolipoprotein B. Proteins linked with Lp(a) concentration were then evaluated for their association with incident CAD risk using Cox proportional hazards models. Significant traits were further included in pathway enrichment analysis. Results Out of 2,920 analyzed proteins (Figure 1), 140 showed a positive association with Lp(a) concentration, while 336 exhibited a negative association after adjustment for multiple testing (False discovery rate &amp;lt; 0.05). The strongest positive associations were observed for apolipoprotein F, group 10 secretory phospholipase A, and C4b-binding protein beta chain. The strongest negative associations were observed for asporin, aminoacylase-1, and retinol-binding protein 5. Among 140 proteins positively associated with Lp(a), 49 were associated with an increased risk of CAD. Conversely, among the 336 proteins negatively associated with Lp(a), 10 were associated with a decreased risk of CAD. Pathway enrichment analysis (Figure 2) indicated that proteins linked with both Lp(a) levels and CAD risk predominantly upregulated pathways related to peptide-ligand receptor signalling, platelet degranulation, neutrophil degranulation, and cytosolic calcium response. Conversely, pathways related to HDL remodeling, PI3K/AKT, KIT, and nuclear receptor signalling were downregulated. Conclusions The greater atherogenic potential of Lp(a) may be attributable to the modulation of several molecular pathways, particularly those involving platelet and neutrophil responses, cell signalling, and lipoprotein metabolism.

Causal relationships between three plasma proteins and non-alcoholic fatty liver disease, mediated by Epstein-Barr virus EA-D antibody levels: a mendelian randomization study

Non-alcoholic fatty liver disease (NAFLD) is a major global health concern, with its prevalence increasing steadily. While plasma proteins have been implicated in NAFLD, establishing causal relationships has been challenging due to confounding factors in observational studies. This study aims to explore the causal relationships between plasma proteins and NAFLD using Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data from multiple sources to conduct MR analyses. Plasma protein data were obtained from the deCODE open database, and NAFLD data were sourced from the Finnish genetic sample collection (FinnGen). We performed MR analysis to identify plasma proteins causally related to NAFLD and explored the potential mediation effect of antibody-immune responses. Our MR analysis identified three plasma proteins—KNG1, MICB, and PKD2—with significant causal relationships to NAFLD. Mediation analysis further revealed that KNG1 negatively mediated the risk of NAFLD through Epstein-Barr virus EA-D antibody levels, while MICB and PKD2 positively mediated NAFLD risk through the same antibody levels. This study provides novel genetic evidence of causal relationships between specific plasma proteins and NAFLD risk. Measuring the levels of KNG1, MICB, PKD2, and Epstein-Barr virus EA-D antibody levels in patients may help clinicians assess NAFLD risk more accurately. Further clinical research is warranted to validate these findings and explore their potential therapeutic implications.

Involvement of Complement in Alzheimer's Disease: From Genetics Through Pathology to Therapeutic Strategies.

Complement is a critical component of innate immunity, evolved to defend against pathogens and clear toxic debris rangingfrom dead and dying cells to immune complexes. These roles make complement a key player in homeostasis; however, complement has a dark side. When the rigid control mechanisms fail, complement becomes dysregulated, acting as a driver of inflammation and resultant pathology in numerous diseases. Roles of complement in Alzheimer's disease (AD) and other dementias have emerged in recent years, supported by genetic, biomarker and pathological evidence and animal model studies. Numerous questions remain regarding the precise roles of complement in the brain in health and disease, including where and when complement is expressed, how it contributes to immune defence and garbage disposal in the healthy brain, and exactly how complement contributes to pathology in dementias. In this brief review, we will summarise current knowledge on complement roles in brain, present the evidence implicating complement in AD and explore whether complement represents an attractive therapeutic target for AD.

Genetic evidence of bidirectional mendelian randomization study on the causality between gut microbiome and respiratory diseases contributes to gut-lung axis

Observational studies and clinical trials have suggested the relationship between the gut microbiome and respiratory diseases, but the causality between them remains unclear. Firstly, we selected eight respiratory diseases Genome-wide association study (GWAS) datasets mainly from the FinnGen collaboration as outcomes. The exposure was based on GWAS statistics about the gut microbiome, sourced from the MiBioGen consortium, including gut microbial taxa. The causal link between the gut microbiome and respiratory illnesses was then estimated using a Two-sample Mendelian randomization (MR) analysis, including the inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode. To ensure reliability, F-statistics and sensitivity tests were conducted. Furthermore, we performed a reverse MR analysis of the pre-Mendelian positive findings to possible reverse causality. For the 196 gut microbe taxa, the IVW analysis suggested 88 potential associations with eight clinically prevalent respiratory diseases. Among them, 30 causal associations were found in more than one MR method. Multiple statistical corrections have confirmed three causal associations: genus Holdemanella was a risk factor for chronic obstructive pulmonary disease (COPD) (P = 1.3 × 10−4, OR = 1.18), family FamilyXIII was a protective factor for COPD (P = 1.3 × 10−3, OR = 0.75), and genus Oxalobacter was a risk factor for asthma (P = 2.1 × 10−4, OR = 1.09). Our MR analysis results indicate that there would be a causal relationship between the gut microbiome and respiratory diseases, contributing to the gut-lung axis. This finding offers new insights into the gut microbiome’s roles in respiratory diseases’ clinical prevention, pathogenesis, and improvement of clinical symptoms. Further randomized controlled trials are necessary to clarify the protective effect of probiotics and fecal microbial transplantation on respiratory health.

Application of Mendelian randomization to explore the genetic association between drinking habits of different beverages and sleep disorder

IntroductionThis study aims to provide genetic evidence linking Drinking Habits of Different Beverages (DHDB) to Sleep Disorder Liability (SDL), potentially informing clinical treatments to improve lifestyle factors.Material and methodsA two-sample Mendelian randomization (MR) method was employed to explore the genetic associations between DHDB and SDL. The DHDB variables studied encompassed Alcohol Intake (ALI), Alcohol Intake Frequency (ALF), High-Frequency Drinking with Meals (HAL), Tea Intake (TEAI), Coffee Intake (COFI), and Red Wine Intake (RWI). The SDL variables analyzed were Insomnia (INS), Inhibit Excitability (IE), and Sleep Duration (SD).ResultsThe MR analysis identified genetic links between ALI and INS, ALF and IE, ALF and SD, HAL and INS, HAL and IE, HAL and SD, TEAI and IE, TEAI and SD, and COFI and IE (P(IVW)&lt;0.05). Nonetheless, no significant genetic links were detected between ALI and IE, ALI and SD, ALF and INS, TEAI and INS, COFI and INS, COFI and SD, RWI and INS, RWI and IE, or RWI and SD (P(IVW)&gt;0.05).ConclusionsAlcohol intake may elevate insomnia risk without affecting daytime sleepiness or sleep duration. Frequent alcohol consumption may lead to daytime sleepiness and reduced sleep duration but not insomnia. Alcohol with meals might reduce insomnia and daytime sleepiness while improving sleep duration. Tea appears unlinked to insomnia and may reduce daytime drowsiness. Coffee may alleviate daytime drowsiness without causing insomnia, and red wine shows no significant association with sleep disorders. Reverse MR suggests potential links between sleep disorders and alcohol or caffeine intake.

Genetic evidence supporting the causal role of 25-hydroxyvitamin D levels in the prognosis of ER- breast cancer: A Mendelian randomization study.

This study aims to investigate the connection between 25-hydroxyvitamin D (25(OH)D) levels and the prognosis of breast cancer with various estrogen receptor (ER) statuses. The summary statistics of 25(OH)D levels was obtained from a GWAS of 441,291 individuals and the information of breast cancer was collected from the Breast Cancer Association Consortium. We analyzed the causal association between 25(OH)D levels and breast cancer prognosis using a number of approaches, including inverse variance weighting (IVW). The heterogeneity test was performed using Cochran Q test. IVW, Mendelian randomization (MR)-Egger, and MR Pleiotropy RESidual Sum and Outlier methods were used for sensitivity analysis. In addition, a multivariate MR adjusted for total triglycerides, total cholesterol, and body mass index was used for further analysis. Two-sample MR results showed that 25(OH)D levels were not associated with prognosis in overall breast cancer (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.73-1.19, IVW exam) and estrogen receptor positive (ER+) breast cancers (OR = 1.12, 95% CI = 0.77-1.63, IVW exam) and were protective associated with prognosis in estrogen receptor negative (ER-) breast cancers (OR = 0.55, 95% CI = 0.34-0.87, IVW exam). Sensitivity analysis did not observe the presence of heterogeneity and horizontal pleiotropy. In multivariate MR analysis, after adjusting for total triglycerides, total cholesterol, and body mass index, the correlation between the protective relationship between 25(OH)D levels and the prognosis for ER- breast cancer remained and became increasingly significant (OR = 0.51, 95% CI = 0.31-0.83, P = .007). This study demonstrated a protective relationship between 25(OH)D levels and the prognosis of ER- breast cancer, but there was no connection between 25(OH)D levels and the prognosis of ER+ breast cancer.

Pan-Draft: automated reconstruction of species-representative metabolic models from multiple genomes

The accurate reconstruction of genome-scale metabolic models (GEMs) for unculturable species poses challenges due to the incomplete and fragmented genetic information typical of metagenome-assembled genomes (MAGs). While existing tools leverage sequence homology from single genomes, this study introduces pan-Draft, a pan-reactome-based approach exploiting recurrent genetic evidence to determine the solid core structure of species-level GEMs. By comparing MAGs clustered at the species-level, pan-Draft addresses the issues due to the incompleteness and contamination of individual genomes, providing high-quality draft models and an accessory reactions catalog supporting the gapfilling step. This approach will improve our comprehension of metabolic functions of uncultured species.

Revisiting the description of Atractoscion macrolepis (Perciformes: Sciaenidae): Another argument for comprehensive taxonomy

Atractoscion macrolepis was described as a species separate to A. aequidens, distinguished by a geographically-separated distribution, genetic evidence and a diagnostic meristic character: the number of pored lateral line scales. However, the distinction of these species and description of A. macrolepis were based on the examination of a limited number of specimens, some of which were incorrectly catalogued and possibly wrongly identified. Moreover, earlier data, demonstrating the overlap of the supposedly diagnostic character, were overlooked or not considered fully. The present study aimed to reconsider the distinction of these two species and to highlight characters for identification, using a more extensive representation of specimens, additional character sets and multivariate analyses. Seven meristic characters, 24 morphometric measurements and nine otolith variables were examined from up to 33 specimens of A. aequidens and 52 specimens of A. macrolepis. These were compared among the species and subjected to univariate and multivariate analyses, including Principal Component Analyses (PCAs) and Discriminant Function Analyses (DFAs). No meristic characters, including the number of lateral line scales, could distinguish the species, with modes being identical or with nodes differing, but ranges overlapping. While the PCA of size-transformed morphometric data revealed some separation of the two species, the DFA indicated significant and reliable discrimination. Considering the otolith variables, the PCA showed weak separation of the two species, while fair discrimination was observed in the DFA. ANOVAs indicated a number of significant differences for some transformed otolith measurements, but there were no clear trends with respect to proportions that would discriminate the species. Further exploration of those morphometric variables highlighted as contributing to separation in the PCA and DFA provided a number of variables that, when expressed as a proportion of SL and used in combination, discriminate A. aequidens and A. macrolepis: HL, MCL, PFL, AFL and PLFL. The present study does not contest the taxonomic status of A. macrolepis, the distinction of which has been demonstrated repeatedly, but does refute the characters regarded as diagnostic. In light of this, an updated key is provided for the five species of the genus. The study demonstrates the value of increased specimen representation and having data fully available rather than in summary.

Causal Association of Folic Acid Supplementary Therapy and Gastric Ulcer: A Mendelian Randomization Study.

Previous research has suggested a potential link between folic acid supplementary therapy and gastric ulcers. To investigate this relationship further, we conducted a Mendelian randomization (MR) analysis using data from the UK Biobank. Our analysis primarily employed inverse variance-weighted (IVW) methods, including both fixed-effect and random-effect models. To ensure the robustness of our findings, additional methods such as the simple median, the weighted median, and the penalized weighted median were also applied. The MR analysis aimed to explore the causal effect of FA supplementary therapy on gastric ulcers. Seven single nucleotide polymorphisms (SNPs) at genetic loci associated with FA supplementary therapy were identified. Both the random-effect and fixed-effect IVW models indicated that genetically predicted FA supplementary therapy significantly reduced the risk of gastric ulcers (OR, 0.870; 95% CI, 0.826-0.917, p<0.001). This result was consistent across other methods, with similar outcomes observed using the simple median (OR, 0.835; 95% CI, 0.773-0.901, p<0.001), the weighted median (OR, 0.854; 95% CI, 0.794-0.919, p<0.001), and the penalized weighted median (OR, 0.849; 95% CI, 0.789-0.914, p<0.001). Leave-one-out sensitivity analysis confirmed that no individual SNP significantly drove the association between FA supplementary therapy and gastric ulcers. This MR study provides genetic evidence that FA supplementary therapy may decrease the risk of gastric ulcers.

The epidemiology of type 1 diabetes mellitus in older adults.

Although type 1 diabetes mellitus (T1DM) is traditionally viewed as a youth-onset disorder, the number of older adults being diagnosed with this disease is growing. Improvements in the average life expectancy of people with T1DM have also contributed to the growing number of older people living with this disease. We summarize the evidence regarding the epidemiology (incidence, prevalence and excess mortality) of T1DM in older adults (ages ≥60 years) as well as the genetics, immunology and diagnostic challenges. Several studies report an incidence peak of T1DM in older adults of a similar size to or exceeding that in children, and population prevalence generally increases with increasing age. Glutamic acid decarboxylase antibody positivity is frequently observed in adult-onset T1DM. Guidelines for differentiating T1DM from type 2 diabetes mellitus in older adults recommend measuring levels of C-peptide and autoantibodies, including glutamic acid decarboxylase antibodies. However, there is no gold standard for differentiating T1DM from type 2 diabetes mellitus in people aged 60 years and over. As such, the global variation observed in T1DM epidemiology might be in part explained by misclassification, which increases with increasing age of diabetes mellitus onset. With a growing global population of older adults with T1DM, improved genetic and immunological evidence is needed to differentiate diabetes mellitus type at older ages so that a clear epidemiological picture can emerge.

A guide to gene-disease relationships in nephrology.

The use of next-generation sequencing technologies such as exome and genome sequencing in research and clinical care has transformed our understanding of the molecular architecture of genetic kidney diseases. Although the capability to identify and rigorously assess genetic variants and their relationship to disease has advanced considerably in the past decade, the curation of clinically relevant relationships between genes and specific phenotypes has received less attention, despite it underpinning accurate interpretation of genomic tests. Here, we discuss the need to accurately define gene-disease relationships in nephrology and provide a framework for appraising genetic and experimental evidence critically. We describe existing international programmes that provide expert curation of gene-disease relationships and discuss sources of discrepancy as well as efforts at harmonization. Further, we highlight the need for alignment of disease and phenotype terminology to ensure robust and reproducible curation of knowledge. These collective efforts to support evidence-based translation of genomic sequencing into practice across clinical, diagnostic and research settings are crucial for delivering the promise of precision medicine in nephrology, providing more patients with timely diagnoses, accurate prognostic information and access to targeted treatments.

Mendelian randomization analysis of the causal relationship between immune cells and keloid

Immune cells play complex roles in the formation of keloid. We aimed to investigate the causal relationship between immune cells and keloid and provide genetic evidence for the association between immune cells and keloid risk. Based on data from GWAS, we performed a comprehensive two-sample Mendelian Randomization (MR) analysis of 731 immune cell traits in 481,912 keloid cases. We used Inverse-Variance Weighted (IVW) method as the primary analysis. Then, a comprehensive sensitivity analysis was adopted to verify the results' robustness, heterogeneity, and horizontal pleiotropy. Finally, reverse MR analysis was performed. The IVW method in forward MR analysis showed that CD66b++ myeloid cell AC was negatively associated with keloid risk (OR &lt; 1, P &lt; 0.05). Consistently, reverse MR analysis showed keloid risk was negatively associated with CD66b++ myeloid cell AC (OR = 0.85, P = 0.012). No significant horizontal pleiotropy or heterogeneity was observed. The results of MR analysis demonstrate a bidirectional causal association between CD66b++ myeloid cell AC and keloid formation, suggesting CD66b++ myeloid cell AC is a protective factor against keloid.