Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes

2020 ◽  
Vol 12 (561) ◽  
pp. eaaz1803
Author(s):  
Sonia García-Calzón ◽  
Alexander Perfilyev ◽  
Mats Martinell ◽  
Monta Ustinova ◽  
Sebastian Kalamajski ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Risk Scores ◽  
Biological Functions ◽  
First Line ◽  
Epigenetic Markers ◽  
Genome Wide ◽  
Drug Naïve ◽  
Epigenetic Pattern

Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.

scholarly journals DNA Methylation and Type 2 Diabetes: the Use of Mendelian Randomization to Assess Causality

2019 ◽  
Vol 7 (4) ◽  
pp. 191-207 ◽  
Author(s):  
Diana L. Juvinao-Quintero ◽  
Marie-France Hivert ◽  
Gemma C. Sharp ◽  
Caroline L. Relton ◽  
Hannah R. Elliott
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Mendelian Randomization ◽  
Epidemiological Studies ◽  
Mendelian Randomisation ◽  
Cross Sectional ◽  
Epigenetic Markers ◽  
Cpg Sites ◽  
Disease Understanding

Abstract Purpose of Review This review summarises recent advances in the field of epigenetics in order to understand the aetiology of type 2 diabetes (T2D). Recent Findings DNA methylation at a number of loci has been shown to be robustly associated with T2D, including TXNIP, ABCG1, CPT1A, and SREBF1. However, due to the cross-sectional nature of many epidemiological studies and predominant analysis in samples derived from blood rather than disease relevant tissues, inferring causality is difficult. We therefore outline the use of Mendelian randomisation (MR) as one method able to assess causality in epigenetic studies of T2D. Summary Epidemiological studies have been fruitful in identifying epigenetic markers of T2D. Triangulation of evidence including utilisation of MR is essential to delineate causal from non-causal biomarkers of disease. Understanding the causality of epigenetic markers in T2D more fully will aid prioritisation of CpG sites as early biomarkers to detect disease or in drug development to target epigenetic mechanisms in order to treat patients.

scholarly journals Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: An analysis of genome-wide DNA methylation

Metabolism ◽  
2014 ◽  
Vol 63 (5) ◽  
pp. 654-660 ◽  
Author(s):  
Melissa C. del Rosario ◽  
Vicky Ossowski ◽  
William C. Knowler ◽  
Clifton Bogardus ◽  
Leslie J. Baier ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Intrauterine Environment ◽  
Genome Wide

scholarly journals Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

2020 ◽  
Author(s):  
Anubha Mahajan ◽  
Cassandra N Spracklen ◽  
Weihua Zhang ◽  
Maggie CY Ng ◽  
Lauren E Petty ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fine Mapping ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Population Diversity ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Diverse Populations ◽  
Genome Wide

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p<5x10-8), including 237 attaining a more stringent trans-ancestry threshold (p<5x10-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

scholarly journals Epigenetic modifications and their role in the development and disease progression of type 2 diabetes

2021 ◽  
Vol 8 (2) ◽  
pp. 948
Author(s):  
Abhijeet Roy
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Epigenetic Regulation ◽  
Association Studies ◽  
Normal Subjects ◽  
Genome Wide Association Studies ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Methylation Patterns

Type 2 Diabetes is one of the major public health issues and a complex metabolic disorder strongly associated with genetic predisposition influenced by environmental factors and epigenetic regulation. This review paper illustrated the role of epigenetics in the pathogenesis, progression, and detection of Type 2 Diabetes. A review study was performed for the articles published in English from 2000-2019 using Pub Med, and Google Scholar databases. Main underlining mechanisms of Type 2 Diabetes were identified; insulin resistance in the peripheral tissue, and disintegrate insulin secretion. Genome Wide Association Studies suggested that epigenetic regulation such as DNA methylation, Histone modification, Non-coding RNA, microRNA is strongly related with the development of Type 2 Diabetes. Altered DNA methylation patterns in pancreatic islets, skeletal muscle, adipose tissue, from diabetic subjects compare to normal subjects was also found. Other risk factors like; obesity, age, gender, impaired glucose tolerance, periconception and intrauterine environment may also have been linked with the possibilities of epigenetic changes. Epigenetics plays a crucial role by modifying the gene expression and establish a relationship between the environment and genetic factors. Understanding the epigenetic mechanisms contributing to the development of Type 2 Diabetes is still limited.

scholarly journals Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits

2019 ◽  
Vol 105 (5) ◽  
pp. 1401-1415 ◽  
Author(s):  
Melis A Aksit ◽  
Rhonda G Pace ◽  
Briana Vecchio-Pagán ◽  
Hua Ling ◽  
Johanna M Rommens ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cystic Fibrosis ◽  
Insulin Sensitivity ◽  
Risk Scores ◽  
Genetic Modifiers ◽  
Β Cell ◽  
Genome Wide ◽  
Independent Population ◽  
A Genome

Abstract Context Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants. Objective To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes. Design and Patients A genome-wide association study was conducted for CFRD onset on 5740 individuals with CF. Weighted polygenic risk scores (PRSs) for type 1 diabetes (T1D), T2D, and diabetes endophenotypes were tested for association with CFRD. Results Genome-wide significance was obtained for variants at a novel locus (PTMA) and 2 known CFRD genetic modifiers (TCF7L2 and SLC26A9). PTMA and SLC26A9 variants were CF-specific; TCF7L2 variants also associated with T2D. CFRD was strongly associated with PRSs for T2D, insulin secretion, postchallenge glucose concentration, and fasting plasma glucose, and less strongly with T1D PRSs. CFRD was inconsistently associated with PRSs for insulin sensitivity and was not associated with a PRS for islet autoimmunity. A CFRD PRS comprising variants selected from these PRSs (with a false discovery rate &lt; 0.1) and the genome-wide significant variants was associated with CFRD in a replication population. Conclusions CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. Two CFRD risk loci are unrelated to T2D and may affect multiple aspects of CF. An 18-variant PRS stratifies risk of CFRD in an independent population.

scholarly journals Polygenic Prediction of Type 2 Diabetes in Africa

2022 ◽  
Author(s):  
Tinashe Chikowore ◽  
Kenneth Ekoru ◽  
Marijana Vujkovic ◽  
Dipender Gill ◽  
Fraser Pirie ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
African American ◽  
Association Studies ◽  
Meta Analysis ◽  
Risk Scores ◽  
Genome Wide Association Studies ◽  
Data Set ◽  
Genome Wide ◽  
Design And Methods

<b>Objective. </b>Polygenic prediction of type 2 diabetes in<b> </b>continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American, European or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans. <p><b>Research Design and Methods</b>. Using the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls. The South African Zulu study (1602 cases and 981 controls) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (2148 cases and 2161 controls).</p> <p> <b>Results. </b>The discriminatory ability of the African American and Multi-ethnic PRS were similar. However<b>, </b>the African American derived PRS was more transferable in all the countries represented in the AADM cohort, and predictive of type 2 diabetes in the country combined analysis compared to the European and multi-ethnic derived scores. Notably, participants in the 10<sup>th</sup> decile of this PRS had a 3.63-fold greater risk (OR 3.63; 95%CI (2.19 - 4.03), p = 2.79 x 10<sup>-17</sup>) per risk allele of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. </p> <p><b>Conclusions </b>African American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in type 2 diabetes.</p>

scholarly journals Genome-Wide Analysis of DNA Methylation Differences in Muscle and Fat from Monozygotic Twins Discordant for Type 2 Diabetes

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e51302 ◽  
Author(s):  
Rasmus Ribel-Madsen ◽  
Mario F. Fraga ◽  
Stine Jacobsen ◽  
Jette Bork-Jensen ◽  
Ester Lara ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Dna Methylation ◽  
Monozygotic Twins ◽  
Genome Wide Analysis ◽  
Genome Wide

scholarly journals Treatment patterns of drug-naive patients with type 2 diabetes mellitus: a retrospective cohort study using a Japanese hospital database

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Yohei Morita ◽  
Hiroki Murayama ◽  
Masato Odawara ◽  
Melissa Bauer
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Real World ◽  
Treatment Patterns ◽  
Treatment Intensification ◽  
First Line ◽  
The Real ◽  
Drug Naïve

Abstract Background Guidelines for Type 2 diabetes mellitus (T2DM) management in Japan provide physicians the discretion to select treatment options based on patient pathophysiology of the disease. There exists a wide variation of preference for initial antidiabetes drugs (AD). The current database analysis aimed to understand the real world treatment patterns in drug-naive patients with T2DM in Japan. Methods We analyzed data of patients (≥ 18 years) diagnosed with T2DM between October 2012 and September 2016 from the Medical Data Vision, a Diagnosis Procedure Combination database. The primary objective was to determine the proportion of T2DM patients receiving each type of treatment as first-line therapy among the drug-naive cohort. Results Of the 436,546 drug-naive patients, 224,761 received their first-line T2DM treatment in the outpatient setting. The mean age of the patient population was 65.6 years at index date. Dipeptidyl peptidase-4 (DPP-4) inhibitor was the most prescribed (56.8%) outpatient AD monotherapy, followed by metformin (15.4%). DPP-4 inhibitors were prescribed over metformin in patients with renal disease (odds ratio [OR]: 4.20; p < 0.0001), coronary heart disease and stroke (OR: 2.22; p < 0.0001). Male (OR: 1.03; p = 0.0026), presence of diabetic complications [retinopathy (OR: 1.33; p < 0.0001), neuropathy (OR: 1.05; p = 0.0037), nephropathy (OR: 1.08; p < 0.0001)] and a high baseline HbA1c (OR: 1.45; p < 0.0001) received treatment intensification during 180 days. Conclusion DPP-4 inhibitors were the most prevalent first-line T2DM treatment followed by metformin in Japan. The findings from this retrospective analysis also support the previously published web survey results and can help understand the real world utilization of T2DM treatment. Trial registration Retrospectively registered

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