Folate and one‐carbon metabolism gene polymorphisms and their associations with oral facial clefts

Abstract

Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.

Maternal methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and risk of nonsyndromic Cleft lip and/or Palate (NSCL/P) in offspring: A meta-analysis

“…Folate has long been considered one such factor in number of observational studies. [2][3][4][5]7,8,15,31 Maternal folic acid supplementation in early pregnancy has been suggested to play a role in the prevention of nonsyndromic orofacial cleft, i.e. cleft lip with or without cleft palate (CL/P).…”

Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Nonsyndromic Cleft Lip and/or Palate

“…Martinelli et al (11) investigated the association between NSCL/P and TCN2 (776C>G) gene in a case-parent triad and they suggested that this polymorphism might be functionally related with NSCL/P. On the other hand, later studies tried to replicate their findings, but could not confirm this association (10).…”

“…Metabolically, just after cellular uptake, cobalamin participates as a cofactor in so many biochemical pathways, including that responsible by homocysteine (Hcy) metabolism, involving methionine, a recognized methyl donor (9). This reaction is regulated by two enzymes, methionine synthase (MTR) and methionine synthase reductase (MTRR), encoded by the MTRR gene (10).…”

MALDI-TOF MS Genotyping of Polymorphisms Related to 1-Carbon Metabolism Using Common and Mass-Modified Terminators

“…We recently published a PinPoint method for the simultaneous detection of 12 polymorphisms related to the 1-carbon metabolism (31 ), which has been used in large-scale epidemiological studies including more than 20 000 samples (3,32,33 ). Here we describe an improved version that includes 20 genetic variants related to 1-carbon metabolism.…”