Investigations of the human MTHFD1 promoter, folate response and neural tube defect risk

Abstract

Nutritional genomics seeks to identify and understand interactions between nutrients and the genome and how these can influence individual susceptibility or resistance to common disease. Gene-nutrient interactions are particularly evident in relation to the B vitamin folate since folate deficiency and disruptions to folate metabolism have been extensively associated with a number of common complex diseases and congenital anomalies. MTHFD1 is a cytoplasmic, trifunctional enzyme with an important role in folate metabolism. A common polymorphism in the MTHFD1 gene, resulting in an arginine to glutamate transition in the enzyme (R653Q), is a maternal risk factor for neural tube defects (NTDs), abruptio placentae, and mid-trimester miscarriage in the Irish population, although its underlying fianctional effect remains elusive (Brody et al, 2002; Parle-McDermott et al., 2005(a); Parle-McDermott et al., 2005(b); Parle-McDermott et al., 2006). Therefore, MTHFD1 is a key gene for further investigation in relation to disease risk and molecular characterisation of how this gene is regulated and factors affecting its expression was the focus of this thesis. This involved characterisation of the promoter region, identification of genetic variants in regulatory regions, investigation of their potential functionality and association with NTD risk, and examination of the response of MTHFD1 and other folate-related genes to folate status.