The C677T Methylenetetrahydrofolate Reductase Polymorphism and Insulin Resistance in Childhood Cancer Survivors.

Childhood cancer survivors have increased risk for cardiovascular disease and insulin resistance. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and low folate are associated with higher levels of homocysteine and changes in methylation status; these factors, in particular the TT and CT genotypes have been associated with insulin resistance in animal and human models. The CT genotype is present in about 25 % of the healthy US population. Vitamin B12 is an important co-factor in this association. The homocysteine/methionine ratio has been used as an indirect marker of methylation status and MTHFR function.

This analysis includes children (n=156) who survived ≥ 5-yrs following diagnosis of acute lymphoblastic leukemia (ALL) (n=55), acute myeloid leukemia (AML) (n=4), and non-Hodgkin's lymphoma (NHL) (n=13), central nervous system tumors (38) and other cancers (n=46). Mean age at diagnosis was 10.3 yrs (5.7-15.8) and mean age at evaluation was 15.0 yrs (9.9-17.9). Anthropometric measurements, blood pressure (BP), fasting glucose, insulin, lipids, folate, vitamin B12, homocysteine, and methionine were collected. Insulin resistance was assessed by euglycemic hyperinsulinemic clamp, adjusted for lean body mass (low Mlbm represents insulin resistance, less than 50% of distribution). Genetic polymorphisms, of MTHFR CC (wildtype) CT (heterozygous) and TT (homozygous) were identified; comparisons between MTHFR polymorphisms were adjusted for age, gender, and Tanner stage.

CC genotype was present in 44%, CT in 47.3 %, and TT in 8.7 % of survivors. Folate and B12 levels were lowest in the TT group, although not statistically significant (P value >0.05). Insulin resistance was most prevalent in the CT group and least prevalent in the TT group. The homocysteine/ methionine ratio was lowest in the CT group and highest in the TT group. Measures of adiposity were similar in all three groups (Table).

This study suggests an increased frequency of the CT genotype in this study population of childhood cancer survivors compared to the healthy US population. Insulin resistance was most prevalent in the CT group; however, this was not associated with low levels of folate, B12, or high homocysteine/methionine ratio. The low frequency of insulin resistance in the TT group likely reflects the small number of participants with this genotype. Further study of these variables in larger populations is needed to provide sufficient power in assessing these relationships in childhood cancer survivors.

No relevant conflicts of interest to declare.