scholarly journals Identification of loci where DNA methylation potentially mediates genetic risk of type 1 diabetes

2018 ◽  
Author(s):  
Jody Ye ◽  
Tom G Richardson ◽  
Wendy L McArdle ◽  
Caroline L Relton ◽  
Kathleen M Gillespie ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Epigenetic Mechanism ◽  
Childhood And Adolescence ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Causal Pathway ◽  
Using Data

AbstractThe risk of Type 1 Diabetes (T1D) comprises both genetic and environmental components. We investigated whether genetic susceptibility to T1D could be mediated by changes in DNA methylation, an epigenetic mechanism that potentially plays a role in autoimmune diabetes. Using data from a non-diabetic population comprising blood samples taken at birth (n=844), childhood (n=911) and adolescence (n=907), we evaluated the associations between 65 top GWAS single nucleotide polymorphisms (SNPs) and genome-wide DNA methylation levels. We identified 159 proximal SNP-cytosine phosphate guanine (CpG) pairs (cis), and 7 distal SNP-CpG associations (trans) at birth, childhood, and adolescence. There was also a systematic enrichment for methylation related SNPs to be associated with T1D across the genome, after controlling for genomic characteristics of the SNPs, implying that methylation could either be on the causal pathway to T1D or a non-causal biomarker. Combining the principles of Mendelian Randomization and genetic colocalization analysis, we provided evidence that at 5 loci,ITGB3BP,AFF3,PTPN2,CTSHandCTLA4, DNA methylation is potentially on the causal pathway to T1D.

scholarly journals Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

2010 ◽  
Vol 3 (1) ◽  
Author(s):  
Christopher G Bell ◽  
Andrew E Teschendorff ◽  
Vardhman K Rakyan ◽  
Alexander P Maxwell ◽  
Stephan Beck ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Dna Methylation ◽  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Type 1 Diabetes Mellitus ◽  
Methylation Analysis ◽  
Genome Wide ◽  
Dna Methylation Analysis

scholarly journals Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0134654 ◽  
Author(s):  
Jean-François Gautier ◽  
Raphaël Porcher ◽  
Charbel Abi Khalil ◽  
Naima Bellili-Munoz ◽  
Lila Sabrina Fetita ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Type 1 Diabetes ◽  
In Utero ◽  
Adult Offspring ◽  
Kidney Dysfunction ◽  
Genome Wide

scholarly journals Epigenetic Changes Induced by Maternal Factors during Fetal Life: Implication for Type 1 Diabetes

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 887
Author(s):  
Ilaria Barchetta ◽  
Jeanette Arvastsson ◽  
Luis Sarmiento ◽  
Corrado M. Cilio
Keyword(s):  
Dna Methylation ◽  
Type 1 Diabetes ◽  
Environmental Factors ◽  
Autoimmune Diseases ◽  
Epigenetic Mechanism ◽  
Fetal Life ◽  
Epigenetic Changes ◽  
Maternal Factors ◽  
Immune Mediated

Organ-specific autoimmune diseases, such as type 1 diabetes, are believed to result from T-cell-mediated damage of the target tissue. The immune-mediated tissue injury, in turn, is known to depend on complex interactions between genetic and environmental factors. Nevertheless, the mechanisms whereby environmental factors contribute to the pathogenesis of autoimmune diseases remain elusive and represent a major untapped target to develop novel strategies for disease prevention. Given the impact of the early environment on the developing immune system, epigenetic changes induced by maternal factors during fetal life have been linked to a likelihood of developing an autoimmune disease later in life. In humans, DNA methylation is the epigenetic mechanism most extensively investigated. This review provides an overview of the critical role of DNA methylation changes induced by prenatal maternal conditions contributing to the increased risk of immune-mediated diseases on the offspring, with a particular focus on T1D. A deeper understanding of epigenetic alterations induced by environmental stressors during fetal life may be pivotal for developing targeted prevention strategies of type 1 diabetes by modifying the maternal environment.

scholarly journals Imprinted loci may be more widespread in humans than previously appreciated and enable limited assignment of parental allelic transmissions in unrelated individuals

2017 ◽  
Author(s):  
Gabriel Cuellar Partida ◽  
Charles Laurin ◽  
Susan M. Ring ◽  
Tom R. Gaunt ◽  
Caroline L. Relton ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Epigenetic Mechanism ◽  
Childhood And Adolescence ◽  
The Novel ◽  
Time Points ◽  
Parents And Children ◽  
Genome Wide ◽  
Parent Of Origin ◽  
Dominance Pattern ◽  
Genomic Regions

AbstractGenomic imprinting is an epigenetic mechanism leading to parent-of-origin dependent gene expression. So far, the precise number of imprinted genes in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at 3 time points (birth, childhood and adolescence) and GWAS data in 740 Mother-Child duos from the Avon Longitudinal Study of Parents and Children (ALSPAC) to systematically identify imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 35 novel and 50 known imprinted regions (10−10< P <10−300). Among the novel loci, we observed signals near genes implicated in cardiovascular disease (PCSK9), and Alzheimer’s disease (CR1), amongst others. Most of the significant regions exhibited imprinting patterns consistent with uniparental expression, with the exception of twelve loci (including the IGF2, IGF1R, and IGF2R genes), where we observed a bipolar-dominance pattern. POEs were remarkably consistent across time points and were so strong at some loci that methylation levels enabled good discrimination of parental transmissions at these and surrounding genomic regions. The implication is that parental allelic transmissions could be modelled at many imprinted (and linked) loci and hence POEs detected in GWAS of unrelated individuals given a combination of genetic and methylation data. Our results indicate that modelling POEs on DNA methylation is effective to identify loci that may be affected by imprinting.

scholarly journals Epigenetic And Transcriptomic Alterations in Offspring Born To Women With Type 1 Diabetes (The EPICOM Study)

2021 ◽  
Author(s):  
Sine Knorr ◽  
Anne Skakkebæk ◽  
Jesper Just ◽  
Christian Trolle ◽  
Søren Vang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Metabolic Disease ◽  
Dna Methylation ◽  
Type 1 Diabetes ◽  
Functional Enrichment ◽  
Postal Code ◽  
Rna Expression ◽  
Increased Risk ◽  
Using Data

Abstract Background: Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease in later in life. In this present study we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease. Design: Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012-2013.Setting: Exploratory sub study using data from the nationwide EPICOM study.Participants: Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex and postal code. Main outcome measures: This study investigates DNA methylation using the 450K-Illumina Infinium assay® and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples. Results: We identified 9 hypermethylated and 5 hypomethylated positions (p < 0.005, |DM-value| > 1). RNA expression profiling identified 38 up- and 1 down-regulated genes (p < 0.005, log2FC ≥ 0.3.). Functional enrichment analysis revealed enrichment in ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling and genes related to T1DM, obesity and atherosclerosis. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX). Conclusions: Findings suggest the possibility for intrauterine hyperglycemia to impact later life methylation and gene expression, a profile that may be linked to the increased risk of metabolic disease.

Type 1 Diabetes-related Autoantibodies in Different Forms of Diabetes

2019 ◽  
Vol 15 (3) ◽  
pp. 199-204 ◽  
Author(s):  
Elin Pettersen Sørgjerd
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Autoimmune Diabetes ◽  
Acid Decarboxylase ◽  
Adult Onset ◽  
Latent Autoimmune Diabetes ◽  
Childhood Type 1 Diabetes ◽  
Childhood Type

Autoantibodies against Glutamic Acid Decarboxylase (GADA), insulinoma antigen-2 (IA- 2A), insulin (IAA) and the most recently Zinc Transporter 8 (ZnT8A) are one of the most reliable biomarkers for autoimmune diabetes in both children and adults. They are today the only biomarkers that can distinguish Latent Autoimmune Diabetes in Adults (LADA) from phenotypically type 2 diabetes. As the frequency of autoantibodies at diagnosis in childhood type 1 diabetes depends on age, GADA is by far the most common in adult onset autoimmune diabetes, especially LADA. Being multiple autoantibody positive have also shown to be more common in childhood diabetes compared to adult onset diabetes, and multiple autoantibody positivity have a high predictive value of childhood type 1 diabetes. Autoantibodies have shown inconsistent results to predict diabetes in adults. Levels of autoantibodies are reported to cause heterogeneity in LADA. Reports indicate that individuals with high levels of autoantibodies have a more type 1 diabetes like phenotype and individuals with low levels of autoantibody positivity have a more type 2 diabetes like phenotype. It is also well known that autoantibody levels can fluctuate and transient autoantibody positivity in adult onset autoimmune diabetes have been reported to affect the phenotype.

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