Association of MTHFR (rs 1801133) gene polymorphism with biochemical markers of B12 deficiency in type 2 diabetes mellitus patients on metformin therapy

Background

Long-term administration of metformin in Type 2 Diabetes mellitus (T2DM), interferes with the absorption of vitamin B12 resulting in deficiency. Low levels of vitamin B12 are associated with cardiovascular morbidity and mortality in T2DM patients. Several genetic variants are associated with vitamin B12 deficiency; one among them is Methylene Tetrahydrofolate reductase (MTHFR). We analyzed MTHFR (rs180133) polymorphism and its association with metformin induced vitamin B12 deficiency in T2DM patients.

Methods

Three hundred T2DM patients were included. For the study and they were screened for vitamin B12 deficiency markers – Methyl malonic acid (MMA), Homocysteine (Hcy) and high sensitive C reactive protein (hsCRP). Genetic variant was analyzed by ARMS-PCR method. Data was analyzed with various statistical tools like ROC, Odds ratio and Likelihood ratio.

Results

There is significant reduction in folic acid and vitamin B12 in metformin users. HsCRP, Hcy and MMA are significantly increased with P < 0.001 in patients with metformin induced B12 deficiency. T allele in MTHFR (T allele ORs =2.1, TT genotype =3.6) showed risk of vitamin B12 deficiency in T2DM patients on metformin therapy. MTHFR gene polymorphism of TT genotype had a Likelihood ratio (LR) of 2.46 for folic acid, 2.77 for MMA and 3.38 for Hcy.

Conclusion

We found an association between MTHFR rs180133, 677C > T and vitamin B12 status in T2DM patients on metformin therapy. Folic acid, MMA and Hcy were found to have high specificity in concordance with MTHFR which showed to be a good predictor for vitamin B12 deficiency in T2DM patients on metformin therapy.