ABSTRACT
Objective: The relationship between diabetes mellitus (DM) and autism spectrum disorder (ASD) remains controversial. This study aimed to analyze the causal relationship between different types of DM and ASD by bidirectional Mendelian randomization (MR). Methods: Single nucleotide polymorphisms for type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), and ASD were obtained from genome-wide association studies. Subsequently, inverse variance weighted, MR-Egger, and weighted median were used to test the exposure-outcome causality. Finally, MR-Egger's intercept, Cochran's Q, and leave-one-out method were used to assess horizontal pleiotropy, heterogeneity, and sensitivity of the results, respectively. Results: The positive analysis showed that T2DM was associated with an increased risk of ASD, whereas neither T1DM nor GDM was associated with the risk of ASD. The reverse analysis showed that ASD was associated with an increased risk of T2DM, while it was not associated with the risk of either T1DM or GDM. MR-Egger intercept showed no horizontal pleiotropy (p > 0.05) for these results. Cochran's Q showed no heterogeneity expect for the results of T1DM on the risk of ASD, and leave-one-out sensitivity analysis showed these results were robust. Conclusion: This MR analysis suggests that T2DM and ASD are reciprocal risk factors and that they may create an intergenerational risk cycling in female patients. Aggressive prevention and treatment of T2DM and ASD help to break the trap of this risk cycling. Additionally, this study does not support a causal relationship between T1DM and ASD, as well as GDM and ASD. And more studies are needed in the future to continue to explore the interactions and underlying mechanisms between different types of DM and ASD.
Subject(s)
Autism Spectrum Disorder , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Diabetes, Gestational , Genome-Wide Association Study , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Humans , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/epidemiology , Autism Spectrum Disorder/etiology , Female , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/complications , Pregnancy , Diabetes, Gestational/genetics , Diabetes, Gestational/epidemiology , Risk Factors , Genetic Predisposition to Disease , MaleABSTRACT
Previous observational studies have identified a link between obesity, adiposity distribution, type 1 Diabetes Mellitus (T1DM), type 2 Diabetes Mellitus (T2DM), and the risk of pressure ulcers (PUs). However, the definitive causality between obesity and PUs, and potential DM mediators remains unclear. Univariable, multivariable, and mediation Mendelian randomization (MR) analyses were conducted to explore the mediating role of T1DM or T2DM in the association between obesity, adiposity distribution, and PUs. Instrumental variables for obesity and adiposity distribution, including Body Mass Index (BMI), waist circumference, hip circumference, trunk fat mass, whole body fat mass, trunk fat percentage, and body fat percentage, were selected from two genome-wide association studies (GWAS). In univariable MR analysis, BMI, hip circumference, and obesity were associated with PUs using inverse variance weighted (IVW) regression. These findings were further corroborated by the replication cohorts and meta-analysis (BMI: OR = 1.537, 95% CI = 1.294-1.824, p < 0.001; Hip circumference: OR = 1.369, 95% CI = 1.147-1.635, p < 0.001; Obesity: OR = 1.235, 95% CI = 1.067-1.431, p = 0.005), respectively. Even after adjusting for confounding factors such as T1DM and T2DM, BMI and hip circumference remained statistically significant in multivariable MR analyses. T2DM may mediate the pathogenesis of BMI-related (OR = 1.106, 95% CI = 1.054-1.160, p = 0.037) and obesity-related PUs (OR = 1.053, 95% CI = 1.034-1.973, p = 0.004). These findings provide insights for the prevention and treatment of PUs, particularly in patients with obesity or DM.
Subject(s)
Adiposity , Body Mass Index , Diabetes Mellitus, Type 2 , Genome-Wide Association Study , Mediation Analysis , Mendelian Randomization Analysis , Obesity , Pressure Ulcer , Humans , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/epidemiology , Obesity/genetics , Obesity/epidemiology , Pressure Ulcer/epidemiology , Pressure Ulcer/etiology , Risk Factors , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/epidemiology , Waist Circumference , MaleABSTRACT
Well-controlled type 1 diabetes (T1DM) is characterized by inflammation and endothelial dysfunction, thus constituting a suitable model of subclinical cardiovascular disease (CVD). miR-199b-5p overexpression in murine CVD has shown proatherosclerotic effects. We hypothesized that miR-199b-5p would be overexpressed in subclinical CVD yet downregulated following metformin therapy. Inflammatory and vascular markers were measured in 29 individuals with T1DM and 20 matched healthy controls (HCs). miR-199b-5p expression in CFU-Hill's colonies was analyzed from each study group, and correlations with inflammatory/vascular health indices were evaluated. Significant upregulation of miR-199b-5p was observed in T1DM, which was significantly downregulated by metformin. miR-199b-5p correlated positively with vascular endothelial growth factor-D and c-reactive protein (CRP: nonsignificant). ROC analysis determined miR-199b-5p to define subclinical CVD by discriminating between HCs and T1DM individuals. ROC analyses of HbA1c and CRP showed that the upregulation of miR-199b-5p in T1DM individuals defined subclinical CVD at HbA1c > 44.25 mmol and CRP > 4.35 × 106 pg/mL. Ingenuity pathway analysis predicted miR-199b-5p to inhibit the target genes SIRT1, ETS1, and JAG1. Metformin was predicted to downregulate miR-199b-5p via NFATC2 and STAT3 and reverse its downstream effects. This study validated the antiangiogenic properties of miR-199b-5p and substantiated miR-199b-5p overexpression as a biomarker of subclinical CVD. The downregulation of miR-199b-5p by metformin confirmed its cardio-protective effect.
Subject(s)
Cardiovascular Diseases , Metformin , MicroRNAs , MicroRNAs/genetics , MicroRNAs/metabolism , Metformin/pharmacology , Metformin/therapeutic use , Humans , Male , Female , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Adult , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Inflammation/genetics , Inflammation/drug therapy , Inflammation/metabolism , Sirtuin 1/metabolism , Sirtuin 1/genetics , C-Reactive Protein/metabolism , C-Reactive Protein/genetics , Middle Aged , Gene Expression Regulation/drug effects , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Jagged-1 Protein/metabolism , Jagged-1 Protein/genetics , Biomarkers , Case-Control StudiesABSTRACT
Cathepsin G (CTSG) plays an important role in the regulation of immune processes. Accumulated studies show that CTSG is involved in the onset and development of type 1 diabetes mellitus (T1DM). As the genetic background of T1DM varies widely among populations, we aimed to study the relationship between genetic polymorphisms in CTSG and T1DM susceptibility in Chinese populations. A total of 141 patients with T1DM and 200 healthy controls were enrolled in the study. Serum CTSG expression was detected using enzyme-linked immunosorbent assay (ELISA). Genotyping of two selected single nucleotide polymorphisms (SNPs) (rs2236742 and rs2070697) of CTSG was performed using PCR and Sanger sequencing. CTSG expression in patients with T1DM was significantly higher than in the control group. Alleles C and T of CTSG SNP rs2236742 were increased in T1DM. No significant associations were found for the SNP rs2070697. Our results indicate that the CTSG rs2236742 allele (C/T) is associated with T1DM in Chinese children and may serve as a new biomarker for predicting T1DM susceptibility.
Subject(s)
Alleles , Asian People , Diabetes Mellitus, Type 1 , Genetic Predisposition to Disease , Genotype , Polymorphism, Single Nucleotide , Humans , Diabetes Mellitus, Type 1/genetics , Female , Male , Child , Case-Control Studies , Asian People/genetics , China/epidemiology , Child, Preschool , Gene Frequency , Enzyme-Linked Immunosorbent Assay , Adolescent , Polymerase Chain Reaction , Biomarkers/blood , East Asian PeopleABSTRACT
Background: Observational studies and clinical trials have implicated polyunsaturated fatty acids (PUFAs) in potentially safeguarding against diabetic microvascular complication. Nonetheless, the causal nature of these relationships remains ambiguous due to conflicting findings across studies. This research employs Mendelian randomization (MR) to assess the causal impact of PUFAs on diabetic microvascular complications. Methods: We identified instrumental variables for PUFAs, specifically omega-3 and omega-6 fatty acids, using the UK Biobank data. Outcome data regarding diabetic microvascular complications were sourced from the FinnGen Study. Our analysis covered microvascular outcomes in both type 1 and type 2 diabetes, namely diabetic neuropathy (DN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). An inverse MR analysis was conducted to examine the effect of diabetic microvascular complications on PUFAs. Sensitivity analyses were performed to validate the robustness of the results. Finally, a multivariable MR (MVMR) analysis was conducted to determine whether PUFAs have a direct influence on diabetic microvascular complications. Results: The study indicates that elevated levels of genetically predicted omega-6 fatty acids substantially reduce the risk of DN in type 2 diabetes (odds ratio (OR): 0.62, 95% confidence interval (CI): 0.47-0.82, p = 0.001). A protective effect against DR in type 2 diabetes is also suggested (OR: 0.75, 95% CI: 0.62-0.92, p = 0.005). MVMR analysis confirmed the stability of these results after adjusting for potential confounding factors. No significant effects of omega-6 fatty acids were observed on DKD in type 2 diabetes or on any complications in type 1 diabetes. By contrast, omega-3 fatty acids showed no significant causal links with any of the diabetic microvascular complications assessed. Conclusions: Our MR analysis reveals a causal link between omega-6 fatty acids and certain diabetic microvascular complications in type 2 diabetes, potentially providing novel insights for further mechanistic and clinical investigations into diabetic microvascular complications.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Angiopathies , Mendelian Randomization Analysis , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Diabetic Angiopathies/genetics , Diabetic Angiopathies/epidemiology , Male , Fatty Acids, Unsaturated , Fatty Acids, Omega-3 , Fatty Acids, Omega-6 , Diabetic Retinopathy/genetics , Diabetic Retinopathy/epidemiology , Female , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Diabetic Nephropathies/genetics , Diabetic Neuropathies/etiology , Diabetic Neuropathies/genetics , Middle AgedABSTRACT
BACKGROUND: The associations of risk factors with vascular impairment in type 1 diabetes patients seem more complex than that in type 2 diabetes patients. Therefore, we analyzed the associations between traditional and novel cardiovascular risk factors and vascular parameters in individuals with T1D and modifications of these associations according to sex and genetic factors. METHODS: In a cross-sectional study, we analyzed the association of risk factors in T1D individuals younger than 65 years using vascular parameters, such as ankle brachial index (ABI) and toe brachial index (TBI), duplex ultrasound, measuring the presence of plaques in carotid and femoral arteries (Belcaro score) and intima media thickness of carotid arteries (CIMT). We also used photoplethysmography, which measured the interbranch index expressed as the Oliva-Roztocil index (ORI), and analyzed renal parameters, such as urine albumin/creatinine ratio (uACR) and glomerular filtration rate (GFR). We evaluated these associations using multivariate regression analysis, including interactions with sex and the gene for connexin 37 (Cx37) polymorphism (rs1764391). RESULTS: In 235 men and 227 women (mean age 43.6 ± 13.6 years; mean duration of diabetes 22.1 ± 11.3 years), pulse pressure was strongly associated with unfavorable values of most of the vascular parameters under study (ABI, TBI, Belcaro scores, uACR and ORI), whereas plasma lipids, represented by remnant cholesterol (cholesterol - LDL-HDL cholesterol), the atherogenic index of plasma (log (triglycerides/HDL cholesterol) and Lp(a), were associated primarily with renal impairment (uACR, GFR and lipoprotein (a)). Plasma non-HDL cholesterol was not associated with any vascular parameter under study. In contrast to pulse pressure, the associations of lipid factors with kidney and vascular parameters were modified by sex and the Cx37 gene. CONCLUSION: In addition to known information, easily obtainable risk factor, such as pulse pressure, should be considered in individuals with T1D irrespective of sex and genetic background. The associations of plasma lipids with kidney function are complex and associated with sex and genetic factors. The decision of whether pulse pressure, remnant lipoproteins, Lp(a) and other determinants of vascular damage should become treatment targets in T1D should be based on the results of future clinical trials.
Subject(s)
Carotid Intima-Media Thickness , Connexins , Diabetes Mellitus, Type 1 , Gap Junction alpha-4 Protein , Humans , Female , Male , Cross-Sectional Studies , Middle Aged , Adult , Connexins/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/epidemiology , Sex Factors , Genetic Predisposition to Disease , Diabetic Angiopathies/genetics , Diabetic Angiopathies/diagnosis , Diabetic Angiopathies/physiopathology , Diabetic Angiopathies/epidemiology , Diabetic Angiopathies/blood , Risk Factors , Ankle Brachial Index , Polymorphism, Genetic , Heart Disease Risk Factors , Glomerular Filtration Rate , Risk Assessment , Photoplethysmography , PhenotypeABSTRACT
Replacement of beta cells through transplantation is a potential therapeutic approach for individuals with pancreas removal or poorly controllable type 1 diabetes. However, stress and death of beta cells pose significant challenges. Circulating miRNA has emerged as potential biomarkers reflecting early beta cell stress and death, allowing for timely intervention. The aim of this study was to identify miRNAs as potential biomarkers for beta cell health. Literature review combined with small RNA sequencing was employed to select islet-enriched miRNA. The release of those miRNA was assessed by RT-qPCR in vivo, using a streptozotocin induced diabetes mouse model and in vitro, through mouse and human islets exposed to varying degrees of hypoxic and cytokine stressors. Utilizing the streptozotocin induced model, we identified 18 miRNAs out of 39 candidate islet-enriched miRNA to be released upon islet stress in vivo. In vitro analysis of culture supernatants from cytokine and/or hypoxia stressed islets identified the release of 45 miRNAs from mouse and 8 miRNAs from human islets. Investigation into the biological pathways targeted by the cytokine- and/or hypoxia-induced miRNA suggested the involvement of MAPK and PI3K-Akt signaling pathways in both mouse and human islets. We have identified miRNAs associated with beta cell health and stress. The findings allowed us to propose a panel of 47 islet-related human miRNA that is potentially valuable for application in clinical contexts of beta cell transplantation and presymptomatic early-stage type 1 diabetes.
Subject(s)
Diabetes Mellitus, Experimental , Islets of Langerhans , MicroRNAs , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , Humans , Mice , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Islets of Langerhans/metabolism , Insulin-Secreting Cells/metabolism , Real-Time Polymerase Chain Reaction/methods , Stress, Physiological/genetics , Male , RNA-Seq/methods , Mice, Inbred C57BL , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/metabolismABSTRACT
Background: There has been controversy and uncertainty regarding the causal relationship between type 1 diabetes, its consequences, liver fibrosis, and cirrhosis. In order to determine the causal relationship, we conducted a Mendelian randomization study (MR). Methods: For the first time, we subjected multiple diabetes data to analyze its relationship with the progression of liver fibrosis. Once the instrumental variables had been extracted, we assessed them employing Cochran's Q multi-analysis, inverse variance weighted, MR-Egger, MR-PRESSO, weighted mode, and weighted median. Results: Genetically predicted type 1 diabetes (OR = 1.13, 95% CI: 1.04-1.23, ** P = 3.42 × 10-3), type 1 diabetes without complications (OR = 1.12, 95% CI: 1.03-1.23, * P = 1.26 × 10-2), type 1 diabetes with coma (OR = 1.09, 95% CI: 1-1.18, * P = 4.74 × 10-2), type 1 diabetes with ketoacidosis (OR = 1.07, 95% CI: 1.01-1.13, * P = 1.3 × 10-2), type 1 diabetes with neurological complications (OR = 1.18, 95% CI: 1.11-1.26, *** P = 4.05 × 10-7), type 1 diabetes with ophthalmic complications (OR = 1.16, 95% CI: 1.05-1.28, ** P = 3.06 × 10-3), type 1 diabetes with renal complications (OR = 1.07, 95% CI: 1-1.13, *P = 3.45 × 10-2), type 1 diabetes with other specified/multiple/unspecified complications (OR = 1.12, 95% CI: 1.02-1.23, * P = 1.41 × 10-2) were all associated with an increased risk of liver fibrosis progression. Conclusions: According to our MR investigation, type 1 diabetes and both its acute and chronic implications may increase the likelihood that liver fibrosis could continue to develop. Additionally, type 1 diabetes with neurological and ocular problems is more likely to accelerate the development of liver fibrosis and inflammation, which offers new insights for genetic investigations.
Subject(s)
Diabetes Mellitus, Type 1 , Disease Progression , Liver Cirrhosis , Mendelian Randomization Analysis , Humans , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/complications , Liver Cirrhosis/pathology , Risk Factors , Chronic Disease , Acute DiseaseABSTRACT
Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic ß cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying ß cell-directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in ß-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.
Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1 , Gastrointestinal Microbiome , Genetic Predisposition to Disease , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/genetics , Humans , Animals , Gastrointestinal Microbiome/immunology , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/metabolism , Gene-Environment Interaction , Autoantibodies/immunology , HLA Antigens/genetics , HLA Antigens/immunology , Mice , Disease Models, Animal , Risk FactorsABSTRACT
To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-race and identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.
Subject(s)
Alleles , Diabetes Mellitus, Type 1 , Gene Frequency , Haplotypes , Humans , Brazil/epidemiology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/diagnosis , Male , Female , Child , Adolescent , Adult , Child, Preschool , Young Adult , Genetic Predisposition to Disease , HLA-DRB1 Chains/genetics , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , Age of Onset , Infant , Middle AgedABSTRACT
INTRODUCTION: The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes. RESEARCH DESIGN AND METHODS: Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs. RESULTS: The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education. CONCLUSIONS: This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors in the development of islet autoimmunity and T1D in the Australian environment. TRIAL REGISTRATION NUMBER: ACTRN12613000794707.
Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1 , Humans , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/etiology , Female , Pregnancy , Australia/epidemiology , Prospective Studies , Male , Child , Infant , Infant, Newborn , Risk Factors , Adult , Islets of Langerhans/immunology , Longitudinal Studies , Follow-Up Studies , Prenatal Exposure Delayed Effects/epidemiology , Child, Preschool , Parents , Genotype , HLA Antigens/geneticsABSTRACT
Background: Diabetes ranks among the most widespread diseases globally, with the kidneys being particularly susceptible to its vascular complications. The identification of proteins for pathogenesis and novel drug targets remains imperative. This study aims to investigate roles of circulating inflammatory proteins in diabetic renal complications. Methods: Data on the proteins were derived from a genome-wide protein quantitative trait locus (pQTL) study, while data on diabetic renal complications came from the FinnGen study. In this study, proteome-wide Mendelian randomization (MR) and colocalization analyses were used to assess the relationship between circulating inflammatory proteins and diabetic renal complications. Results: MR approach indicated that elevated levels of interleukin 12B (IL-12B) (OR 1.691, 95%CI 1.179-2.427, P=4.34×10-3) and LIF interleukin 6 family cytokine (LIF) (OR 1.349, 95%CI 1.010-1.801, P=4.23×10-2) increased the risk of type 1 diabetes (T1D) with renal complications, while higher levels of fibroblast growth factor 19 (FGF19) (OR 1.202, 95%CI 1.009-1.432, P=3.93×10-2), fibroblast growth factor 23 (FGF23) (OR 1.379, 95%CI 1.035-1.837, P=2.82×10-2), C-C motif chemokine ligand 7 (CCL7) (OR 1.385, 95%CI 1.111-1.725, P=3.76×10-3), and TNF superfamily member 14 (TNFSF14) (OR 1.244, 95%CI 1.066-1.451, P=5.63×10-3) indicated potential risk factors for type 2 diabetes (T2D) with renal complications. Colocalization analysis supported these findings, revealing that most identified proteins, except for DNER, likely share causal variants with diabetic renal complications. Conclusion: Our study established associations between specific circulating inflammatory proteins and the risk of diabetic renal complications, suggesting these proteins as targets for further investigation into the pathogenesis and potential therapeutic interventions for T1D and T2D with renal complications.
Subject(s)
Diabetic Nephropathies , Mendelian Randomization Analysis , Proteome , Humans , Diabetic Nephropathies/blood , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/etiology , Proteome/metabolism , Proteome/analysis , Male , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/metabolism , Female , Quantitative Trait Loci , Genome-Wide Association Study , Inflammation/blood , Inflammation/metabolism , Fibroblast Growth Factors/blood , Fibroblast Growth Factors/genetics , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/genetics , Biomarkers/blood , Middle AgedABSTRACT
Types diabetes other than type 1 are generally considered rare in children and adolescents. The incidence of type 2 diabetes has increased dramatically over the past decade in some ethnic groups. The increased incidence of this type of diabetes mellitus has corresponded tem-porally to unprecedented increases in body weight and obesity prevalence in adolescents in various ethnic populations. Early treatment of insulin resistance is important to prevent the development of diabetes. In therapy, lifestyle modification is essential for weight loss, and if this is not enough, pharmacotherapy is required. Maturity-onset diabetes of the young (MODY), another type of insulin-dependent diabetes, is characterised by early onset and autosomal dominant inheritance. MODY is mainly caused by ß-cell defects, resulting in insufficient insulin secretion for a given blood glucose level. Unlike non-insulin-dependent diabetes in youth (NIDDM-Y), there is no significant increase in insulin resistance. The purpose of this article is to characterise and present types of diabetes other than type 1 found in the young population.
Subject(s)
Diabetes Mellitus, Type 2 , Humans , Adolescent , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/therapy , Child , Male , Female , Diabetes Mellitus, Type 1/therapy , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/genetics , Insulin Resistance , Prevalence , IncidenceABSTRACT
Type I diabetes is an autoimmune disease mediated by T-cell destruction of ß cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes. As most strongly associated variants are noncoding, there is still a lack of identification of functional and, therefore, likely causal variants. Given that many of these genetic variants reside in enhancer elements, we have tested 121 CD4+ T-cell enhancer variants associated with T1D. We found four to be functional through massively parallel reporter assays. Three of the enhancer variants weaken activity, while the fourth strengthens activity. We link these to their cognate genes using 3D genome architecture or eQTL data and validate them using CRISPR editing. Validated target genes include CLEC16A and SOCS1. While these genes have been previously implicated in type 1 diabetes and other autoimmune diseases, we show that enhancers controlling their expression harbor functional variants. These variants, therefore, may act as causal type 1 diabetic variants.
Subject(s)
CD4-Positive T-Lymphocytes , Diabetes Mellitus, Type 1 , Enhancer Elements, Genetic , Genetic Predisposition to Disease , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Humans , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Enhancer Elements, Genetic/genetics , Suppressor of Cytokine Signaling 1 Protein/genetics , Genome-Wide Association Study , Lectins, C-Type/genetics , Genetic Variation , Polymorphism, Single Nucleotide , Quantitative Trait LociABSTRACT
BACKGROUD: Previous observational studies have shown that vitiligo usually co-manifests with a variety of dysglycemic diseases, such as Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM). Mendelian randomization (MR) analysis was performed to further evaluate the causal association between fasting plasma glucose, glycosylated hemoglobin (HbA1c), T1DM, T2DM and vitiligo. MATERIALS AND METHODS: We used aggregated genome-wide association data from the Integrative Epidemiology Unit (IEU) online database of European adults vitiligo; HbA1c data were from IEU. Fasting blood glucose data were obtained from the European Bioinformatics Institute (EBI). T1DM and T2DM data were from FinnGen. We used bidirectional two-sample and multivariate MR analyses to test whether dysglycemic measures (fasting blood glucose, HbA1c), diabetes-related measures (T1DM, T2DM) are causatively associated with vitiligo. Inverse variance weighting (IVW) method was used as the main test method, MR-Egger, Weighted mode and Weighted median were used as supplementary methods. RESULTS: We found no statistically significant evidence to support a causal association between dysglycemic traits and vitiligo, but in the correlation analysis of diabetic traits, our data supported a positive causal association between T1DM and vitiligo (p = 0.018). In the follow-up multivariate MR analysis, our results still supported this conclusion (p = 0.016), and suggested that HbA1c was not a mediator of T1DM affecting the pathogenesis of vitiligo. No reverse causality was found in any of the reverse MR Analyses of dysglycemic traits and diabetic traits. CONCLUSIONS: Our findings support that T1DM is a risk factor for the development of vitiligo, and this conclusion may explain why the co-presentation of T1DM and vitiligo is often seen in observational studies. Clinical use of measures related to T1DM may be a new idea for the prevention or treatment of vitiligo.
Subject(s)
Blood Glucose , Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Genome-Wide Association Study , Glycated Hemoglobin , Mendelian Randomization Analysis , Vitiligo , Vitiligo/genetics , Vitiligo/blood , Vitiligo/epidemiology , Humans , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/epidemiology , Glycated Hemoglobin/metabolism , Risk Factors , Adult , Male , FemaleABSTRACT
Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5'-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10-16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10-3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.
Subject(s)
Antigens, CD , Codon, Initiator , Genetic Predisposition to Disease , Lymphocyte Activation Gene 3 Protein , Humans , Codon, Initiator/genetics , Antigens, CD/genetics , Antigens, CD/metabolism , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Female , Polymorphism, Single Nucleotide , Vitiligo/genetics , Male , Genome-Wide Association Study , Thyroiditis, Autoimmune/genetics , 5' Untranslated Regions/genetics , Case-Control Studies , Iceland , AdultABSTRACT
BACKGROUND AND AIMS: Primary biliary cholangitis (PBC) is an autoimmune disease often accompanied by multisystem damage. This study aimed to explore the causal association between genetically predicted PBC and diabetes, as well as multiple cardiovascular diseases (CVDs). METHODS: Genome-wide association studies (GWAS) summary data of PBC in 24,510 individuals of European ancestry from the European Association for the Study of the Liver was used to identify genetically predicted PBC. We conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to estimate the impacts of PBC on diabetes (N = 17,685 to 318,014) and 20 CVDs from the genetic consortium (N = 171,875 to 1,030,836). RESULTS: SVMR provided evidence that genetically predicted PBC is associated with an increased risk of type 1 diabetes (T1D), type 2 diabetes (T2D), myocardial infarction (MI), heart failure (HF), hypertension, atrial fibrillation (AF), stroke, ischemic stroke, and small-vessel ischemic stroke. Additionally, there was no evidence of a causal association between PBC and coronary atherosclerosis. In the MVMR analysis, PBC maintained independent effects on T1D, HF, MI, and small-vessel ischemic stroke in most models. CONCLUSION: Our findings revealed the causal effects of PBC on diabetes and 7 CVDs, and no causal relationship was detected between PBC and coronary atherosclerosis.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 1 , Genome-Wide Association Study , Liver Cirrhosis, Biliary , Mendelian Randomization Analysis , Humans , Liver Cirrhosis, Biliary/genetics , Liver Cirrhosis, Biliary/complications , Cardiovascular Diseases/genetics , Cardiovascular Diseases/etiology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/complications , Atrial Fibrillation/genetics , Myocardial Infarction/genetics , Myocardial Infarction/epidemiology , Hypertension/complications , Hypertension/genetics , Heart Failure/genetics , Stroke/genetics , Stroke/etiology , Stroke/epidemiologyABSTRACT
BACKGROUND: Studies in epidemiology have indicated a link between chronic obstructive pulmonary disease (COPD) and various autoimmune conditions.This study aimed to investigate the potential causal link between nine autoimmune diseases with a genetic basis and COPD using a two-sample Mendelian randomization (MR) analysis. METHOD: To test the impact of susceptibility to immune-related outcomes on genetic prediction of COPD risk, we used pooled statistics from the largest genome-wide association study (GWAS) in Europe in a two-sample MR setting.Genetic data for type 1 diabetes, hypothyroidism, systemic lupus erythematosus, and primary biliary cirrhosis were obtained from the European Bioinformatics Institute (EBI), while data for multiple sclerosis and primary sclerosing cholangitis were extracted from the Integrative Epidemiology Unit (IEU) database. Additionally, genetic data for ulcerative colitis, rheumatoid arthritis, and celiac disease were also collected.These nine autoimmune diseases and the COPD cohort from the UK Biobank (1605 cases and 461,328 controls) were analyzed separately as exposure and outcome.Our primary method for the initial screening was inverse variance weighting (IVW).The MR-Egger regression test assessed multivariate validity, while the Cochran's Q test examined heterogeneity.To ensure the reliability of the findings, a leave-one-out analysis was conducted. RESULT: IVW discovered proof of type 1 diabetes (OR = 1.0003; 95 % CI = 1.0000-1.0005; P = 0.046), hypothyroidism (OR = 1.0004; 95 % CI = 1.0001-1.0008; P = 0.0263), celiac disease (OR = 1.0002; 95 % CI = 1.0000-1.0004; P = 0.0168) and systemic lupus erythematosus (OR = 1.0002; 95 % CI = 1.0000-1.0004; P = 0.049) were significantly linked to the heightened risk of COPD with no signs of variation or pleiotropy.Even after accounting for potential confounding factors like smoking, the correlation remained robust.Additionally, our research found that the IVW method did not indicate any causal link between COPD and multiple sclerosis, ulcerative colitis, rheumatoid arthritis, primary biliary cirrhosis, or primary sclerosing cholangitis (all P >0.05). CONCLUSION: This research discovered that individuals with type 1 diabetes, hypothyroidism, celiac disease, and systemic lupus erythematosus have a higher likelihood of developing COPD.Additionally, this research revealed no connection between COPD and multiple sclerosis, ulcerative colitis, rheumatoid arthritis, primary biliary cirrhosis, or primary sclerosing cholangitis.
Subject(s)
Autoimmune Diseases , Genome-Wide Association Study , Mendelian Randomization Analysis , Pulmonary Disease, Chronic Obstructive , Humans , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/epidemiology , Autoimmune Diseases/genetics , Autoimmune Diseases/epidemiology , Genetic Predisposition to Disease , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/epidemiology , Liver Cirrhosis, Biliary/genetics , Liver Cirrhosis, Biliary/epidemiology , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.
Subject(s)
Forkhead Transcription Factors , Genetic Diseases, X-Linked , Genetic Therapy , Germ-Line Mutation , Interleukin-10 , T-Lymphocytes, Regulatory , Animals , Forkhead Transcription Factors/genetics , Mice , Interleukin-10/genetics , Interleukin-10/immunology , Genetic Therapy/methods , T-Lymphocytes, Regulatory/immunology , Genetic Diseases, X-Linked/therapy , Genetic Diseases, X-Linked/immunology , Genetic Diseases, X-Linked/genetics , Interleukins/immunology , Interleukins/genetics , Diarrhea/genetics , Diarrhea/therapy , Diarrhea/immunology , Intestinal Diseases/immunology , Intestinal Diseases/genetics , Intestinal Diseases/therapy , Dependovirus/genetics , Mice, Inbred C57BL , Immune System Diseases/immunology , Immune System Diseases/therapy , Immune System Diseases/genetics , Immune System Diseases/congenital , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/therapy , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/congenital , Mice, Knockout , Lymphocyte Activation/immunology , Humans , Interleukin-27/geneticsABSTRACT
BACKGROUND: Clinical studies have shown that cardiovascular diseases in patients with type 1 diabetes (T1D) are often atypical or asymptomatic. The link between T1D and arrhythmia remains unclear. To infer causality between T1D and arrhythmia at the genetic level, we conducted a Mendelian randomization study through the genetic tools of T1D. METHODS: In this study, we used genetic variables and summary statistics from genome-wide association studies of T1D and arrhythmia. Single nucleotide polymorphisms were selected based on the assumptions of instrumental variables. The inverse variance-weighted method was used as the primary analysis to summarize the causal effects between exposure and outcome. The weighted median and weighted mode methods were used as secondary methods. We tested for horizontal pleiotropy using the MR-Egger method and detected heterogeneity using the Q-test. A leave-one-out sensitivity analysis was performed. Scatter plots, forest plots, and funnel plots were used to visualize the results of the MR analysis. RESULTS: In this study, we selected 28 T1D-related SNPs as instrumental variables. The IVW [odds ratio (OR) = 0.98, 95 % confidence interval (CI) = 0.97-1.00, P = 0.008], weighted median (OR = 0.98, 95 % CI = 0.96 - 0.99, P = 0.009), and weighted mode (OR = 0.98, 95 % CI = 0.96-0.99, P = 0.018) analysis methods suggested a causal effect of T1D on arrhythmia. The MR-Egger method indicated no horizontal pleiotropy (P = 0.649), and the Q-test showed no heterogeneity (IVW, P = 0.653). CONCLUSIONS: Our MR analysis revealed a causal association between T1D and the development of arrhythmia, indicating that patients with T1D had a higher risk of arrhythmia.