Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms and protection from microvascular complications in adolescents with type 1 diabetes

Abstract

Folate status has been associated with endothelial dysfunction in adolescents with type 1 diabetes, and elevated total plasma homoocyst(e)ine (tHcy) is a risk for vascular disease in the non-diabetic population. Polymorphisms in genes involved in folate and homocysteine metabolism are implicated in vascular disease. We aimed to determine whether polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes are risk factors for early microvascular disease in a large group of adolescents with type 1 diabetes. Four hundred and eighty adolescents were screened annually for retinopathy and microalbuminuria for a median of 4 yr. Molecular analysis for the polymorphisms 677C-->T, 1298A-->C in MTHFR, and 66A-->G in MTRR was performed. The MTRR 66GG genotype reduced the risk for elevated albumin excretion rate (AER) (OR 0.47, CI 0.25, 0.88, p = 0.018) and showed a trend to reduced risk for microalbuminuria (OR 0.27, CI 0.06-1.21, p = 0.09). Survival without elevated AER was increased with the MTRR 66GG genotype (12.4 vs. 9.7 yr, p = 0.04) and with the MTHFR 1298CC genotype (15.2 vs. 10.2 yr, p = 0.007). Conversely, survival without retinopathy was reduced with the MTHFR 677TT and MTRR 66GG combined genotype (6.2 vs. 10.2 yr, p = 0.015). The MTRR 66GG and MTHFR 1298 CC genotypes may confer protection against early nephropathy, possibly because they are associated with lower tHcy. The MTHFR 677 TT was only related to earlier onset retinopathy in combination with MTRR 66GG.

A NOS3 Polymorphism Determines Endothelial Response to Folate in Children with Type 1 Diabetes or Obesity

“…[18][19][20] We have shown an association between polymorphisms in MTHFR and MTRR and onset of elevated albumin excretion rate in children with type 1 diabetes. 21 We have previously shown that endothelial dysfunction in children with type 1 diabetes relates to red cell folate (RCF), 8 and in intervention studies folate improves 22 or normalizes 23 endothelial function in children with type 1 diabetes, but not with obesity. 24 However, there are no studies assessing the interaction between endothelial response to folate and NOS3 polymorphisms, which may explain individual variations in response.…”

A Perspective on Nutritional Genomics

“…[79][80][81] In the C>T mutation, individuals have a higher height, weight, body mass index, obesity index, arm circumference, fat mass, fat distribution, carotid intimamedia thickness, and tHcy level than individuals with a normal genotype. MTHFR genotype may be useful in predicting the development of premature coronary artery disease, especially in hypertensive adolescents.…”

“…26 Poor folate status has been associated with endothelial dysfunction in adolescents with type 1 diabetes. 79 The MTHFR A>C genotype may confer protection against early nephropathy with lower tHcy levels, whereas MTHFR 677 TT genotypes may have earlier onset of retinopathy. 79 The MTHFR C>T polymorphism has a significant association with diabetic neuropathy in whites and in persons with type 2 diabetes.…”

“…79 The MTHFR A>C genotype may confer protection against early nephropathy with lower tHcy levels, whereas MTHFR 677 TT genotypes may have earlier onset of retinopathy. 79 The MTHFR C>T polymorphism has a significant association with diabetic neuropathy in whites and in persons with type 2 diabetes. 95 More rigorous studies are needed to define the role of genotypes in diabetes complications and management.…”

Homocysteine in the Pathogenesis of Chronic Glaucoma

“…It has been suggested that homozygous mutation of MTHFR is associated with premature onset of diabetic retinopathy only in the presence of homozygous methionine synthase reductase mutation. 63 However, in a case series from Turkey, 64 no association between MTHFR C677T mutation and HHcy with retinopathy or neuropathy could be found. It is unclear whether such differences reflect ethnic variation, result from differences in study design or are influenced by other unidentified factors.…”