Abstract
The aim of this study is to quantify global DNA methylation and investigate the relationship with diabetes status and polymorphisms in MTHFR C677T and NOS3 G894T genes in mixed ancestry subjects from South Africa. Global DNA methylation was measured, and MTHFR rs1801133 and NOS3 rs1799983 polymorphisms were genotyped using high throughput real-time polymerase chain reaction and direct DNA sequencing. Of the 564 participants, 158 (28%) individuals had T2DM of which 97 (17.2%) were screen-detected cases. Another 119 (21.1%) had prediabetes, that is, impaired fasting glucose, impaired glucose tolerance, or the combination of both, and the remainder 287 (50.9%) had normal glucose tolerance. Global DNA methylation was significantly higher in prediabetes and screen-detected diabetes than in normal glucose tolerance (both p ≤ 0.033) and in screen-detected diabetes compared to known diabetes on treatment (p = 0.019). There was no difference in global DNA methylation between known diabetes on treatment and normal glucose tolerance (p > 0.999). In multivariable linear regression analysis, only NOS3 was associated with increasing global DNA methylation (β = 0.943; 95% CI: 0.286 to 1.560). The association of global DNA methylation with screen-detected diabetes but not treated diabetes suggests that glucose control agents to some extent may be reversing DNA methylation. The association between NOS3 rs1799983 polymorphisms and DNA methylation suggests gene-epigenetic mechanisms through which vascular diabetes complications develop despite adequate metabolic control.
Highlights
Type 2 diabetes mellitus (T2DM) results from an interaction of environmental and genetic factors
Global DNA methylation (%) was significantly higher in subjects with prediabetes or diabetes when compared to individuals with normoglycemia (p < 0.05)
Our results show that global DNA methylation is increased in both prediabetic and diabetic states, but this increase was more pronounced in those with screen-detected diabetes, even after adjustment for extraneous factors such as age, gender, smoking, and glucose tolerance status
Summary
Type 2 diabetes mellitus (T2DM) results from an interaction of environmental and genetic factors. Despite the initial enthusiasm from the identification of risk loci for T2DM [1, 2], the clinical utility of these genetic markers for T2DM risk prediction and reduction has remained limited. It is becoming increasingly evident that the gene-environment interaction in T2DM and other diseases can be explained in part by epigenetics. A number of recent studies using different types of biological tissues from pancreas to peripheral blood mononuclear cells (PBMCs) are showing that DNA methylation patterns are altered in subjects with diabetes [3,4,5,6]. T2DM rates are increasing rapidly in African populations, with traditional diabetes risk factors failing to explain a great deal of these increases.
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