rs2236225

rs2236225, also known as c.1958G>A, G1958A, p.Arg653Gln and R653Q, is a SNP in the MTHFD1 gene on chromosome 14, involved in folate metabolism. The Arg653Gln mutation was studied and found not to affect the enzyme activity when present, but did seem to decrease the half-life and stability. A study in Quebec showed an association in children with mutations in MTHFD1 having increased risk for heart defects, possibly in a folate status dependent manner (IE more so if their mother was not getting enough folate during pregnancy). A 2014 meta-analysis of nine studies totaling 4,302 cases of children born with neural tube defects concluded that Caucasian mothers carrying rs2236225(C;T) or rs2236225(T;T) alleles were at increased risk, of about 1.5 - 1.7x, of having affected children compared to mothers with no (T) alleles. However, they cautioned that their results should be "viewed with caution" given the statistical uncertainties inherent in these studies. rs1076991 C > T exerts a significant effect on promoter activity in vitro and along with rs2236225 G > A influences embryonic development. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. Common genetic polymorphisms affect the human requirement for the nutrient choline. Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline. Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts. Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population. Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate. Genetic polymorphisms in methyl-group metabolism and epigenetics: lessons from humans and mouse models. Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study. No association of single nucleotide polymorphisms in one-carbon metabolism genes with prostate cancer risk. Lack of association of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma. Genetic variants in phosphatidylethanolamine N-methyltransferase and methylenetetrahydrofolate dehydrogenase influence biomarkers of choline metabolism when folate intake is restricted. Epigenetic mechanisms for nutrition determinants of later health outcomes. Development of a fingerprinting panel using medically relevant polymorphisms. 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects. Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis. Genetics of human neural tube defects. Application of sex-specific single-nucleotide polymorphism filters in genome-wide association data. Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project. Maternal polymorphisms in folic acid metabolic genes are associated with nonsyndromic cleft lip and/or palate in the Brazilian population. Folate and choline metabolism gene variants and development of uterine cervical carcinoma. Polymorphic variants of genes involved in homocysteine metabolism in celiac disease. Folate and choline metabolism gene variants in relation to ovarian cancer risk in the Polish population.

A;G

Some studies, predominanty amongst Caucasians, have shown that presence of this mutation is associated with a slightly higher risk to give birth to children with neural tube defects; other studies have demonstrated association with heart defects in homozygous offspring - See discussion at rs2236225.

A;A

There is a slightly higher risk (~1.5x at most) for Caucasian mothers with this genotype to give birth to children with neural tube defects; see discussion at rs2236225.