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

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.

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The Expression Level of mRNA, Protein, and DNA Methylation Status of FOSL2 of Uyghur in XinJiang in Type 2 Diabetes

Journal of Diabetes Research ◽

10.1155/2016/5957404 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Jun Li ◽

Siyuan Li ◽

Ying Hu ◽

Guolei Cao ◽

Siyao Wang ◽

...

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Dna Methylation ◽

Methylation Status ◽

Methylation Data ◽

Biochemical Indicators ◽

Expression Levels ◽

Protein Levels ◽

Cpg Sites

Objective. We investigated the expression levels of both FOSL2 mRNA and protein as well as evaluating DNA methylation in the blood of type 2 diabetes mellitus (T2DM) Uyghur patients from Xinjiang. This study also evaluated whether FOSL2 gene expression had demonstrated any associations with clinical and biochemical indicators of T2DM. Methods. One hundred Uyghur subjects where divided into two groups, T2DM and nonimpaired glucose tolerance (NGT) groups. DNA methylation of FOSL2 was also analyzed by MassARRAY Spectrometry and methylation data of individual units were generated by the EpiTyper v1.0.5 software. The expression levels of FOS-like antigen 2 (FOSL2) and the protein expression levels were analyzed. Results. Significant differences were observed in mRNA and protein levels when compared with the NGT group, while methylation rates of eight CpG units within the FOSL2 gene were higher in the T2DM group. Methylation of CpG sites was found to inversely correlate with expression of other markers. Conclusions. Results show that a correlation between mRNA, protein, and DNA methylation of FOSL2 gene exists among T2DM patients from Uyghur. FOSL2 protein and mRNA were downregulated and the DNA became hypermethylated, all of which may be involved in T2DM pathogenesis in this population.

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Novel epigenetic determinants of type 2 diabetes in Mexican-American families

Human Molecular Genetics ◽

10.1093/hmg/ddv232 ◽

2015 ◽

Vol 24 (18) ◽

pp. 5330-5344 ◽

Cited By ~ 75

Author(s):

Hemant Kulkarni ◽

Mark Z. Kos ◽

Jennifer Neary ◽

Thomas D. Dyer ◽

Jack W. Kent ◽

...

Keyword(s):

Type 2 Diabetes ◽

Dna Methylation ◽

Mexican Americans ◽

Mexican American ◽

Fasting Blood Glucose ◽

Phenotypic Traits ◽

High Risk Population ◽

Cpg Sites ◽

Increased Risk

Abstract Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

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The role of circulating galectin-1 in type 2 diabetes and chronic kidney disease: evidence from cross-sectional, longitudinal and Mendelian randomisation analyses

Diabetologia ◽

10.1007/s00125-021-05594-1 ◽

2021 ◽

Author(s):

Isabel Drake ◽

Emanuel Fryk ◽

Lena Strindberg ◽

Annika Lundqvist ◽

Anders H. Rosengren ◽

...

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Diabetic Nephropathy ◽

Kidney Disease ◽

Kidney Function ◽

Mendelian Randomisation ◽

Cross Sectional ◽

Genome Wide

Abstract Aims/hypothesis Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects. Methods Participants (n = 4022; 58.6% women) in the Malmö Diet and Cancer Study–Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 ± 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 ± 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 × 10−11). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort. Results Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 × 10−89) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 × 10−3). Conclusions/interpretation Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement. Graphical abstract

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Is bisphenol A exposure associated with the development of glucose intolerance and increased insulin resistance in Thais?

Nutrition and Health ◽

10.1177/0260106017708730 ◽

2017 ◽

Vol 23 (3) ◽

pp. 185-191 ◽

Cited By ~ 3

Author(s):

La-or Chailurkit ◽

Pechngam Tengpraettanakorn ◽

Suwannee Chanprasertyotin ◽

Boonsong Ongphiphadhanakul

Keyword(s):

Type 2 Diabetes ◽

Glucose Tolerance ◽

Bisphenol A ◽

Epidemiological Studies ◽

Normal Glucose Tolerance ◽

Cross Sectional Study ◽

Oral Glucose ◽

Cross Sectional ◽

Normal Glucose

Bisphenol A (BPA), the monomeric component of polycarbonate plastics, reportedly possesses endocrine-disrupting effects. Exposure to low levels of BPA during more vulnerable periods leads to abnormalities related to sexual development in experimental animals. Moreover, recently a few epidemiological studies in Caucasians have demonstrated the association of BPA exposure with type 2 diabetes. Therefore, in the present study we examined the association of BPA exposure and abnormal glucose tolerance in Thais. This is a cross-sectional study of 240 participants aged at least 50 years, randomly selected by computer-generated random numbers within each glucose tolerance status from an oral glucose tolerance study of 661 participants. There were 80 participants in each group of type 2 diabetes, impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). Serum BPA was measured by competitive ELISA. The detection rate of BPA was significantly higher in participants with IGT compared to those with NGT ( p < 0.05), while no difference was found between participants with type 2 diabetes and NGT. When participants with type 2 diabetes were stratified into those with fasting plasma glucose (FPG) under the diabetic threshold (<126 mg/dL) and those over (≥126 mg/dL), it was found that those with FPG under the diabetic threshold had measurable rates of BPA comparable to those with IGT, and rates significantly higher than the NGT group ( p < 0.05), while those with FPG over the diabetic threshold did not have higher rates of measurable BPA compared with the NGT group. In conclusion, BPA exposure is not uncommon in Thais. There is an association between BPA exposure and IGT, but not type 2 diabetes.

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Study of vitamin d levels in patients with type 2 diabetes mellitus

International Journal of Medical Research and Review ◽

10.17511/ijmrr.2021.i01.02 ◽

2021 ◽

Vol 9 (1) ◽

pp. 13-20

Author(s):

Dr. J.V. Srujan ◽

◽

Dr. Surya Prakash Rao ◽

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Vitamin D ◽

Type 2 Diabetes Mellitus ◽

Epidemiological Studies ◽

Cross Sectional Study ◽

Cross Sectional ◽

Vitamin D Levels ◽

Study Results

Introduction: Diabetes is defined as a disturbance in intermediary metabolism manifesting aschronic sustained hyperglycemia, primarily due to either an absolute or a relative lack of insulin.Many epidemiological studies have demonstrated an inverse relationship between vitamin D levelsand diabetes mellitus. However, there is a paucity of literature regarding the levels of vitamin D intype 2 diabetes, which is common in our community. This study was taken up to shed more light onthis issue. Material and methods: This was a cross-sectional study conducted at NRI Institute ofMedical Sciences, Sangivalasa, Visakhapatnam district. Cases of Type 2 Diabetes Mellitus attendingto the outpatient department, diagnosed as per the ADA criteria of 2011, between the ages of 31and 75 years constituted the material for the present study. Results and conclusion: Vitamin Dlevels were found to be significantly lower in the study group (19.91±7.0 ng/ml) as compared to thecontrol group (32.22±4.0 ng/ml).

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

Science Translational Medicine ◽

10.1126/scitranslmed.aaz1803 ◽

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.

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