Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects.
Folic acid supplementation can effectively reduce the risk of neural tube defects (NTDs); however, the mechanism underlying this beneficial effect remains unclear. Recent evidence suggests that certain folate pathway genes, as well as those related to homocysteine metabolism might be contributing to this effect. The purpose of this study is to investigate whether gene polymorphisms of methionine synthase (MTR) and methionine synthase reductase (MTRR) are involved in the risk for NTDs, specifically spina bifida. We detected MTR A2756G and MTRR A66G polymorphisms using PCR-RFLP analysis in a group of NTD infants, their mothers and normal controls. We found that infants with the MTRR mutant genotype had a 2.6-fold higher risk of NTDs when compared to the AA genotype (OR = 2.6, 95%CI = 1.3-5.3). Mothers with the MTRR mutant genotype also had a 1.9-fold higher risk of having an NTD baby compared to AA genotype (OR = 1.9, 95%CI = 1.1-3.1). Infants who carry mutant alleles for both MTRR and MTR had exceptionally elevated NTD risks, with odds ratios of 5.1 compared to infants with the wild type genotype at both loci (AA + AA) (OR = 5.1, 95%CI = 1.7-15.4). A comparable result was observed in the mothers of NTD cases (OR = 2.1, 95%CI = 1.0-4.7). Our results indicate that MTRR and MTR genes may interact to increase the infants' NTD risks. These results did not appear to be influenced by maternal periconceptional folic acid intake. However,the sample size of this study was limited, and a larger population study is needed to pursue these initial observations.
Zhu
Huiping
H
Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX 77030, USA.
Wicker
Ned J
NJ
Shaw
Gary M
GM
Lammer
Edward J
EJ
Hendricks
Kate
K
Suarez
Lucina
L
Canfield
Mark
M
Finnell
Richard H
RH
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008745:Methylation; D009436:Neural Tube Defects / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length
C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase