Relationship of MTHFR Gene 677C→T Polymorphism, Homocysteine, and Estimated Glomerular Filtration Rate Levels With the Risk of New-Onset Diabetes

Abstract

East Asian patients with diabetes have a higher risk for renal complications and strokes than Europeans. We aimed to evaluate the effect of methylenetetrahydrofolate reductase (MTHFR) gene 677C→T polymorphism, which was associated with a higher stroke risk and was common in the Chinese population, as well as homocysteine and estimated glomerular filtration rate (eGFR) levels on the risk of new-onset diabetes (NOD).A total of 2422 subjects without diabetes were followed-up for 7 years. NOD was defined as fasting plasma glucose ≥7.0 mmol/L or self-reported physician diagnosis of diabetes.Compared with subjects with MTHFR 677CC genotype, those with TT genotype had a higher risk of NOD in females (odds ratio 2.78, 95% confidence interval 1.39–5.56) but not in males (0.80, 0.40–1.61, P for interaction = 0.008). Furthermore, MTHFR 677C→T polymorphism was more strongly associated with the risk of NOD among females with higher body mass index (BMI, ≥23 vs <23 kg/m2, P for interaction = 0.009) or lower high-density lipoprotein-cholesterol (HDL-C, <1.3 vs ≥1.3 mmol/L, P for interaction = 0.015) levels. Hyperhomocysteinemia (≥16 vs <10 μmol/L) was not significantly associated with NOD in males (0.88, 0.42–1.85) or females (1.52, 0.65–3.57). However, mildly decreased eGFR (<90 vs 90–120 mL/min/1.73 m2) was associated with NOD mainly in males (1.96, 1.01–3.78; females, 0.74, 0.32–1.72, P for interaction = 0.134).Females with MTHFR 677TT genotype had a significantly higher risk of NOD, particularly those with higher BMI or low HDL-C levels. The higher risk of NOD associated with mildly decreased eGFR also warrants more investigation. Our results provide insights into the ethnic differences of diabetic complications between East Asian patients and Europeans.

Additive Interaction of MTHFR C677T and MTRR A66G Polymorphisms with Being Overweight/Obesity on the Risk of Type 2 Diabetes

“…Its etiology is complicated because this disease involves multiple genetic and environmental factors and their interactions [4]. Methylenetetrahydrofolate reductase ( MTHFR ) and methionine synthase reductase ( MTRR ) have been suggested as candidate genes for studying the association with T2D [5,6,7]. …”

Tagging Functional Polymorphism in 3’ Untranslated Region of Methylene Tetrahydrofolate Reductase and Risk of Ischemic Stroke

“…Functional polymorphisms in the exon region of the MTHFR have been shown to be associated with the pathogenesis of IS. For example, the rs1801133 polymorphism was associated with reductions in MTHFR activity of approximately 70% and 35% in TT and CT genotype carriers, respectively, leading to increased levels of tHcy, which predicted a poor prognosis among IS patients [14-16]. The A1298C variant resulted in substitution of glutamate (Glu) by alanine (Ala) at codon 429 in the S-adenosylmethionine regulatory domain of the MTHFR protein [17-19].…”

Methylene Tetrahydrofolate Reductase (MTHFR) rs868014 Polymorphism Regulated by miR-1203 Associates with Risk and Short Term Outcome of Ischemic Stroke

“…Previous studies demonstrated an association of MTHFR genetic variants in gene coding regions with ischemic stroke risk [15, 18, 19]. In this study, we mainly focused on the relationship of the SNPs in the MTHFR 3'-UTR to ischemic stroke risk and outcome.…”

“…MTHFR is localized at chromosome 1 p36.3 in the human genome, and to date there are over 40 point mutations or SNPs in the MTHFR gene identified [14]. Of these, C677T (rs1801133) and A1298C (rs1801131) are the most significant mutations that associate with ischemic stroke [15, 16]. The MTHFR rs1801133 polymorphism involves substitution of C to T at position 677 (C677T), causing the conversion of alanine to valine.…”