Global DNA hypomethylation is associated with NTD-affected pregnancy: A case-control study.
BACKGROUND
Neural tube defects are severe, common birth defects that result from failure of neural tube closure. They are considered to be a multifactorial disorder, and our knowledge of causal mechanisms remains limited. We hypothesized that abnormal DNA methylation occurs in NTD-affected fetuses. The correlations of global DNA methylation levels with complexity of NTDs and known risk factors of NTDs, MTHFR genotype and fever, were analyzed.


METHODS
A hospital-based case-control study was performed. Epidemiologic data, pathologic diagnosis, and methylenetetrahydrofolate reductase (MTHFR) genotype analysis were completed. Array comparative genomic hybridization was used to exclude cytogenetic abnormalities. Global DNA methylation statuses were determined for both brain and skin tissue.


RESULTS
Sixty-five NTD-affected fetuses and 65 normal controls matched for gestational and maternal ages were collected. In brain tissue, global DNA methylation levels were significantly decreased in cases compared with controls (4.12 vs. 4.99%; p < 0.001). DNA hypomethylation (<4.35%) resulted in a significant 5.736-fold increased risk for NTDs (95% confidence interval, 1.731-19.009; p = 0.004). Nonisolated NTDs had lower levels of global DNA methylation than did isolated NTDs (3.77 vs. 4.70%; p = 0.022). After stratifying subjects by MTHFR genotype, we observed a skewed distribution of global DNA methylation levels. For genotype C/C, global DNA methylation status was the same in the two groups (4.51 vs. 4.72%; p = 0.687). For T/T, cases had significantly lower global methylation levels than did controls (5.23 vs. 3.79%; p < 0.001).


CONCLUSIONS
Global DNA hypomethylation in fetal brain tissue was associated with NTD-affected pregnancy. DNA methylation levels were correlated with NTD complexity. The MTHFR genotype contributed to global DNA hypomethylation. Birth Defects Research (Part A), 2010. (c) 2010 Wiley-Liss, Inc.
Chen
Xiaoli
X
Department of Molecular Immunology, Capital Institute of Pediatrics, Beijing, China.
Guo
Jin
J
Lei
Yunping
Y
Zou
Jizhen
J
Lu
Xiaolin
X
Bao
Yihua
Y
Wu
Lihua
L
Wu
Jianxin
J
Zheng
Xiaoying
X
Shen
Yiping
Y
Wu
Bai-Lin
BL
Zhang
Ting
T
D000328:Adult; D016022:Case-Control Studies; D002681:China; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009436:Neural Tube Defects / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D012307:Risk Factors; D011795:Surveys and Questionnaires
D042965:Methylenetetrahydrofolate Reductase (NADPH2)