MTHFR Gene Polymorphism as a Risk Factor for Diabetic Retinopathy in Type 2 Diabetic Patients Without Serum Creatinine Elevation

Diabetic retinopathy (DR), a serious microangiopathic complication of diabetes, is the leading cause of catastrophic loss of vision in Japan. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in remethylation of homocysteine to methionine. A point mutation (C677T) in the MTHFR gene leads to impaired activity and is the most common genetic determinant of moderate hyperhomocysteinemia in the general population (1). Neugebauer et al. (2) reported a significantly higher prevalence of the mutant allele in diabetic patients with retinopathy. However, in their study, patients with retinopathy showed severe renal failure with higher levels of serum creatinine compared with those without retinopathy. Considering that renal failure accelerates atherosclerosis, we investigated the relationship between the MTHFR genotype and DR in 156 type 2 diabetic patients with <133 μmol/l serum creatinine level. According to international standards, patients with retinopathy in each genotype were classified into three groups: no DR (NDR), nonproliferative DR (NPDR), and proliferative DR (PDR). Their genotypes were analyzed using the PCR-restriction fragment–length polymorphism method (3).

The allelic frequency of the C677T mutation was 0.40. Genotype frequencies were in accordance with the Hardy-Weinberg equation (677C/677C, 35.3%, n = 55; 677C/677T, 50.0%, n = 78; 677T/677T, 14.7%, n = 23; χ² test, P = 0.9995). Statistical analyses showed no association of genotypes with clinical parameters such as sex, age, known diabetes duration, BMI, HbA_1c, fasting blood glucose, total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, and creatinine (data not shown). The frequency of 677T/677T homozygous patients with retinopathy was the highest among the three genotypes (677T/677T, 60.9%; 677C/677T, 25.6%; 677C/677C, 32.7%; χ² test, P = 0.007). The frequency of 677T/677T homozygous patients with NPDR was the highest among the three genotypes (677T/677T, 39.2%; 677C/677T, 17.9%; 677C/677C, 18.2%; χ² test, P = 0.03). This implies that the first signs of DR could appear earlier in 677T/677T homozygous patients than in those with the other two genotypes. These data indicate that the 677T/677T mutation in the MTHFR gene could be an independent risk factor for retinopathy. Based on the previous reports that hyperhomocysteinemia induces endothelial dysfunction, causing angiopathy (4), it is possible that the decrease in serum homocysteine level, such as with a high-folate diet, prevents the onset of DR, especially in diabetic patients with the C677T mutation. In summary, presence of the MTHFR genotype in diabetic patients can be a predictive marker of the progression of DR. Additionally, it is proposed that treatment for diabetes based on the MTHFR gene polymorphism could delay the progression of DR.