Evaluation of infant methylenetetrahydrofolate reductase genotype, maternal vitamin use, and risk of high versus low level spina bifida defects.
BACKGROUND
Several studies have suggested that homozygosity for the C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) variant is a potential risk factor for neural tube defects (NTDs), as individuals homozygous for the C677T allele have slightly elevated homocysteine concentrations under conditions of low folic acid intake. It has been hypothesized that maternal folic acid supplementation prevents NTDs by partially correcting reduced MTHFR activity associated with the variant form of the enzyme.


METHODS
Genomic DNA was extracted from newborn screening blood spots obtained from 145 infants with spina bifida (SB) and 260 nonmalformed control infants. The MTHFR C677T genotype was determined by restriction enzyme digestion of PCR amplification products with Hinf1. We investigated whether infant MTHFR genotype influenced the risk for the anatomic level of the SB lesion (high vs. low); we also explored whether maternal vitamin use influenced this risk.


RESULTS
Compared to controls, the frequency of SB infants with the homozygous 677 TT genotype was greatest in those infants with high level SB defects (26%; odds ratio [OR] = 2.9; 95% confidence interval [CI] = 0.9-10.1) than for those with low level SB defects (22%; OR = 1.8; 95% CI = 0.9-3.2). Furthermore, homozygous 677TT infants whose mothers did not use vitamins containing folic acid had a modestly increased risk of SB (OR = 1.8; 95% CI = 0.8-3.9), with this risk increasing more than three-fold (OR = 5.5; 95% CI = 0.8-28.1) for those infants with high level SB defects whose mothers did not use vitamins.


CONCLUSIONS
Based upon our observations, it is suggested that the association between the infant MTHFR homozygous variant genotype and spina bifida risk may be conditional upon both lesion level and maternal vitamin use.
Volcik
Kelly A
KA
Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030-0330, USA. kvolcik@ibt.tamu.edu
Shaw
Gary M
GM
Lammer
Edward J
EJ
Zhu
Huiping
H
Finnell
Richard H
RH
D002140:California / Q000453:epidemiology; D016022:Case-Control Studies; D004247:DNA / Q000032:analysis; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D016017:Odds Ratio; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012306:Risk; D016135:Spinal Dysraphism / Q000097:blood / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control
D004247:DNA; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)