Genetic polymorphism of methylenetetrahydrofolate reductase as a risk factor for diabetic nephropathy in Chinese type 2 diabetic patients

Abstract

Objective: Genetic predisposition has been implicated in diabetic nephropathy (DN). The C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene, one of the key enzymes catalyzing remethylation of homocysteine, may play a role in the development of not only vascular disease but also diabetic microangiopathies. In this study, we examined the distribution of the MTHFR genotypes in the Chinese population and the association between the C677T variant and diabetic nephropathy. Methods: 220 unrelated patients with type 2 diabetes mellitus and 130 controls were recruited. The MTHFR genotype was analyzed by PCR followed by HinfI digestion. Plasma total homocysteine levels were measured using high-performance liquid chromatography (HPLC) with fluorescence detection. Results: In 130 healthy control subjects, the frequency of the mutant T allele was 30.0%, comparable to that of a Hong Kong (Chinese) population. The distribution of the three genotypes was as follows: TT genotype, 16.9%; CT genotype, 26.2%; and CC genotype, 56.9%. This genotype distribution did not differ between control subjects and type 2 diabetic patients in which 19.1% were TT, 34.5% were CT and 46.4% were CC (χ2=3.85, P>0.05). The frequency of the mutant T allele was 42.3% in diabetic patients with nephropathy (n=124) versus 28.6% in those without nephropathy (n=96). The genotype frequencies were TT, 21.0%; CT, 42.7%; CC, 36.3% in diabetic patients with nephropathy versus TT, 16.7%; CT, 23.9%; CC, 59.4% in those without nephropathy. The MTHFR genotype and allele frequencies were different between diabetic patients with and without nephropathy (χ2=12.27, P<0.005; χ2=8.77, P<0.005, respectively). Moreover, plasma homocysteine levels were markedly higher in individuals with TT genotype than those with CC or CT genotype. Conclusions: The C677T mutation of MTHFR gene is common in the Chinese population. MTHFR C677T gene polymorphism associated with a predisposition to increased plasma homocysteine levels may represent a genetic risk factor for diabetic nephropathy in Chinese type 2 diabetic patients.