Are the betaine‐homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts?

Abstract

Abnormalities in folate and/or homocysteine metabolism may adversely influence embryonic development, leading to the birth of infants with a variety of congenital malformations, including neural tube defects (NTDs) and craniofacial abnormalities. Based upon suggestive evidence that periconceptional folic acid supplementation is effective in preventing a significant proportion of the aforementioned birth defects, genetic variation in the folate biosynthetic pathways may influence the infant's susceptibility to these birth defects. The goal of our study was to investigate sequence variations in the betaine-homocysteine methyltransferase (BHMT) and betaine-homocysteine methyltransferase (BHMT2) genes as modifiers of risk of spina bifida, cleft palate, and cleft lip and palate. The results of this study indicated that individuals homozygous for the single nucleotide polymorphism R239Q in BHMT did not have elevated risks for spina bifida. Genotype frequencies for the BHMT2 rs626105 polymorphism also did not reveal any elevated risks for spina bifida, and only a modest, imprecise elevation of risk for orofacial clefts. The results of these experiments suggest that variants of the BHMT/BHMT2 genes in infants do not substantially contribute to the risk of spina bifida or orofacial clefts in our study population.

Nonsynonymous Polymorphisms in Genes in the One-Carbon Metabolism Pathway and Associations with Colorectal Cancer

“…(50,51) and spina bifida (52) associated with Gln/Gln versus Arg/Arg at BHMT codon 239 have been suggested among three previous studies. However, another study observed no association with spina bifida (53), and Arg 239 Gln has not been associated with altered BHMT activity (51) or homocysteine levels (50). Although the evidence for an association between BHMT Arg 239 Gln and homocysteine-related diseases is weak, the suggested reduced risks of cardiovascular disease and spina bifida is in contrast to the increased risk of colorectal cancer due to the Gln allele that we observed.…”

Folate‐mediated one‐carbon metabolism and neural tube defects: Balancing genome synthesis and gene expression

“…One common variant in the BHMT gene, A742G, has been identified; however, two independent studies failed to detect a significant association with NTD risk (Morin et al, 2003b;Zhu et al, 2005). The BHMT A742G SNP has not shown a strong relationship with homocysteine levels (Weisberg et al, 2003;Ananth et al, 2007), indicating that it may not have functional relevance.…”

Choline and betaine in health and disease

“…BHMT c.716G>A was found not to be related to plasma tHcy concentration (Fredriksen et al 2007;Heil et al 2000;Morin et al 2003;Weisberg et al 2003), but a recent large epidemiological study demonstrated decrease in dimethylglycine (the product of the BHMT reaction) according to the number of c.716A alleles (Fredriksen et al 2007), suggesting that this polymorphism may have metabolic effects. The variant c.716A allele has been associated with increased risk (Morin et al 2003), decreased risk (Boyles et al 2006), or no change in risk (Zhu et al 2005) of spina bifida, and decreased risk of coronary artery disease and no association with risk of cardiovascular disease (Heil et al 2000) or aortic aneurysm (Giusti et al 2008). Furthermore, carriers of the variant allele have been reported to have increased risk of colorectal cancer (Koushik et al 2006) and possibly decreased risk of colorectal adenoma when combined with high methyl status (Hazra et al 2007).…”