Effect of MTHFR (rs1801133) and FTO (rs9939609) genetic polymorphisms and obesity in T2DM: a study among Bengalee Hindu caste population of West Bengal, India.
TL;DR: The risk of Type 2 diabetes mellitus (T2DM) susceptibility has increased due to the independent risks of genetic polymorphism and obesity as well as combinations of these as mentioned in this paper.
Abstract: Type 2 diabetes mellitus (T2DM) susceptibility has increased due to the independent risks of genetic polymorphism and obesity as well as combinations of these. Despite recent advancements in T2DM m...
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TL;DR: In this article , a review summarizes the current knowledge and gaps about m6A and m6Am modifications and their respective regulators in the pathophysiology of type 2 diabetes mellitus and its treatment by metformin, the first-line antidiabetic agent.
Abstract: The rapidly developing research field of epitranscriptomics has recently emerged into the spotlight of researchers due to its vast regulatory effects on gene expression and thereby cellular physiology and pathophysiology. N6-methyladenosine (m6A) and N6,2’-O-dimethyladenosine (m6Am) are among the most prevalent and well-characterized modified nucleosides in eukaryotic RNA. Both of these modifications are dynamically regulated by a complex set of epitranscriptomic regulators called writers, readers, and erasers. Altered levels of m6A and also several regulatory proteins were already associated with diabetic tissues. This review summarizes the current knowledge and gaps about m6A and m6Am modifications and their respective regulators in the pathophysiology of diabetes mellitus. It focuses mainly on the more prevalent type 2 diabetes mellitus (T2DM) and its treatment by metformin, the first-line antidiabetic agent. A better understanding of epitranscriptomic modifications in this highly prevalent disease deserves further investigation and might reveal clinically relevant discoveries in the future.
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TL;DR: In this community-based sample of U.S. adults, higher adiponectin levels were associated with a lower incidence of diabetes, and the association was of similar magnitude in men and women and in whites and African Americans, but was absent in smokers and in those with a greater inflammation score.
Abstract: Adipocyte-derived secretory proteins have been increasingly linked to diabetes. To investigate whether adiponectin, a major adipocyte secretory protein, predicts diabetes, we conducted a case-cohort study representing the approximately 9-year experience of the 10,275 middle-aged, U.S. African-American and white participants of the Atherosclerosis Risk in Communities (ARIC) study. Adiponectin was measured on stored plasma of 581 incident diabetes case subjects and 572 noncase subjects. Overall hazard ratios (95% CIs) for developing diabetes, for those in the second, third, and fourth (versus the first) quartile of adiponectin were 0.57 (0.41-0.78), 0.39 (0.27-0.56), and 0.18 (0.11-0.27), respectively, after adjustment for age, sex, ethnicity, study center, parental history of diabetes, and hypertension and 0.72 (0.48-1.09), 0.67 (0.43-1.04), and 0.58 (0.34-0.99), respectively, after additional adjustment for BMI, waist-to-hip ratio, fasting glucose, insulin, and a score composed of six inflammation markers. The association was of similar magnitude in men and women and in whites and African Americans, but was absent in smokers and in those with a greater inflammation score (interaction P < 0.01 for each). In conclusion, in this community-based sample of U.S. adults, higher adiponectin levels were associated with a lower incidence of diabetes.
345 citations
TL;DR: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI, and the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions is highlighted.
Abstract: Objective: Common variation in the FTO gene is associated with body mass index (BMI) and type 2 diabetes. Increased BMI is associated with diabetes risk factors including raised insulin, glucose and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits. Research design and methods: We tested the association between FTO genotype and ten metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO -BMI and BMI-trait associations. Results: Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039SD [95%CI:0.013-0.064]; P =0.003), glucose (0.024SD [0.001-0.048]; P =0.044), and triglycerides (0.028SD [0.003-0.052]; P =0.025), and lower HDL-cholesterol (0.032SD [0.008-0.057]; P =0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine-aminotransferase, gamma-glutamyl-transferase and LDL-cholesterol, HbA1c and systolic and diastolic blood pressure were in the expected direction but did not reach P FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio:1.17 [95%CI:1.10-1.25]; P =3×10 −6 ). Conclusions: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of greater than 12,000 individuals were needed to detect associations at P
310 citations
Medical Research Council1, Lund University2, Umeå University3, Utrecht University4, University of Paris-Sud5, Wellcome Trust Sanger Institute6, University of Cambridge7, University of Helsinki8, German Cancer Research Center9, Imperial College London10, Aarhus University11, Aalborg University12, University of Naples Federico II13, International Agency for Research on Cancer14, University of Oxford15
TL;DR: The InterAct case-cohort study investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association.
Abstract: Aims/hypothesis
Although family history of type 2 diabetes (T2D) is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study we investigated the association of family history of diabetes among different family members with incidence of T2D and the extent to which genetic, anthropometric and lifestyle risk factors mediated this association.
231 citations
TL;DR: This study replicates the strong association of FTO variants with type 2 diabetes and similar to the study in North Indians Sikhs, shows that this association may not be entirely mediated through BMI.
Abstract: Aims and hypothesis
Variants of the FTO (fat mass and obesity associated) gene are associated with obesity and type 2 diabetes in white Europeans, but these associations are not consistent in Asians. A recent study in Asian Indian Sikhs showed an association with type 2 diabetes that did not seem to be mediated through BMI. We studied the association of FTO variants with type 2 diabetes and measures of obesity in South Asian Indians in Pune.
181 citations
TL;DR: The association between FTO SNP rs9939609 and obesity risk may decline at older age, and the variant affects circulating adiponectin and leptin levels through the changes in BMI.
Abstract: Objective: To examine the longitudinal association of FTO variant with obesity, circulating adipokine levels, and FTO expression in various materials from human and mouse. Research Design and Methods: We genotyped rs9939609 in 2,287 men and 3,520 women from two prospective cohorts. Plasma adiponectin and leptin were measured in a subset of diabetic men (n=854) and women (n=987). Expression of FTO was tested in adipocytes from db/db mice and mouse macrophages. Results: We observed a trend toward decreasing associations between rs9939609 and BMI at older age (≥65 y) in men, whereas the associations were constant across different age groups in women. In addition, SNP rs9939609 was associated with lower plasma adiponectin [log(e)- means: 1.82±0.04, 1.73±0.03, and 1.68±0.05 for TT, TA, and AA genotypes; P for trend=0.02] and leptin (log(e)- means: 3.56±0.04, 3.63±0.04, and 3.70±0.06; P for trend=0.06] in diabetic women. Adjustment for BMI attenuated the associations. FTO gene was universally expressed in human and mice tissues, including adipocytes. In an ancillary study of adipocytes from db/db mice, FTO expression was ∼50% lower than those from wild-type mice. Conclusions: The association between FTO SNP rs9939609 and obesity risk may decline at older age. The variant affects circulating adiponectin and leptin levels through the changes in BMI. In addition, the expression of FTO gene was reduced in adipocytes from db/db mice.
146 citations