A case-parent triad assessment of folate metabolic genes and the risk of childhood acute lymphoblastic leukemia

Abstract

We conducted a case-parent triad study evaluating the role of maternal and offspring genotypes in the folate metabolic pathway on childhood acute lymphoblastic leukemia (ALL) risk. Childhood ALL case-parent triads (n = 120) were recruited from Texas Children's Hospital. DNA samples were genotyped using the Sequenom iPLEX MassARRAY for 68 tagSNPs in six folate metabolic pathway genes (MTHFR, MTRR, MTR, DHFR, BHMT, and TYMS). Log-linear modeling was used to examine the associations between maternal and offspring genotypes and ALL. After controlling for the false discovery rate (<0.1), there were 20 significant maternal effects in the following genes: BHMT (n = 3), MTR (n = 12), and TYMS (n = 5). For instance, maternal genotypes for BHMT rs558133 (relative risk [RR] = 0.51, 95 % confidence interval [CI]: 0.30-0.87, p = 0.008, Q = 0.08) and MTR rs2282369 (RR = 0.46, 95 % CI: 0.27-0.80, p = 0.004, Q = 0.08) were associated with ALL. There were no significant offspring effects after controlling for the false discovery rate. This is one of the few studies conducted to evaluate maternal genetic effects in the context of childhood ALL risk. Furthermore, we employed a family-based design that is less susceptible to population stratification bias in the estimation of maternal genetic effects. Our findings suggest that maternal genetic variation in the folate metabolic pathway is relevant in the etiology of childhood ALL. The observed maternal genetic effects support the need for continued research of how the uterine environment may influence risk of ALL.