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Relationship between polymorphism of methylenetetrahydrofolate dehydrogenase and congenital heart defect
Jun Cheng1, Wen-Li Zhu, Jing-Jing Dao
1Department of Nutrition and Food Hygiene, School of Public Health, Peking university, Beijing 100083, China. wgcj5098@sina.com.cn
Insights
The methylenetetrahydrofolate dehydrogenase (MTHFD) G1958A gene polymorphism did not show a direct link to congenital heart disease (CHD) in North China. However, parental MTHFD G1958A mutations may reduce the risk of arterial septal defects in offspring.
Area of Science:
- Genetics
- Cardiovascular Disease
- Molecular Biology
Background:
- Congenital heart disease (CHD) is a significant global health concern.
- Genetic factors play a crucial role in the etiology of CHD.
- The methylenetetrahydrofolate dehydrogenase (MTHFD) gene is involved in folate metabolism, essential for nucleotide synthesis and DNA repair.
Purpose of the Study:
- To investigate the association between the G1958A gene polymorphism of MTHFD and the occurrence of CHD in a North Chinese population.
- To explore the potential impact of this polymorphism on serum folate and homocysteine levels.
- To determine if parental MTHFD G1958A genotypes influence CHD risk in offspring.
Main Methods:
- Case-control study involving 192 CHD patients and 124 healthy controls from North China.
- Genotyping of the MTHFD G1958A locus using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP).
- Quantification of serum folic acid and homocysteine (Hcy) levels via radio-immunoassay and fluorescence polarization immunoassay (FPIA).
Main Results:
- No significant differences in MTHFD G1958A genotype distribution or allele frequency were found between CHD patients and controls.
- A significantly lower A allele frequency was observed in mothers of arterial septal defect (ASD) patients compared to controls (10.87% vs. 28.15%).
- Parental carriage of the MTHFD G1958A A allele was associated with a reduced risk of ASD in offspring (OR=0.34).
- Serum folic acid levels were significantly higher in CHD patients than controls, while Hcy levels showed no significant difference.
Conclusions:
- The MTHFD G1958A gene polymorphism is not a significant risk factor for CHD in the studied North Chinese population.
- MTHFD G1958A mutation in parents, particularly mothers, may confer a protective effect against arterial septal defects in their children.
- This protective effect might be mediated by increased MTHFD enzyme activity, enhanced folate metabolism, and reduced homocysteine levels.
Objective:
To investigate the relationship between G1958A gene polymorphism of methylenetetrahydrofolate dehydrogenase (MTHFD) and occurrence of congenital heart disease (CHD) in North China.
Methods:
One hundred and ninety-two CHD patients and their parents were included in this study as case group in Liaoning Province by birth defect registration cards, and 124 healthy subjects (age and gender matched) and their parents were simultaneously selected from the same geographic area as control. Their gene polymorphism of MTHFD G1958A locus was examined with PCR-RFLP, and serum folic acid and homocysteine (Hcy) levels were tested with radio-immunoassay and fluorescence polarization immunoassay (FPIA).
Results:
There existed gene polymorphism at MTHFD G1958A locus in healthy subjects living in North China. The percentages of GG, GA, and AA genotype were 57.98%, 35.57%, and 6.45% respectively, and the A allele frequency was 24.23%, which was significantly different from Western population. No difference was observed when comparing genotype distribution and allele frequency between the case and control groups, so was the result from the comparison between genders. The A allele frequency of arterial septal defect patients' mothers (10.87%) was significantly lower than that of controls (28.15%) (P=0.014), with OR=0.31 (95% CI: 0.09-0.84), and no difference in the other subgroups. The percentage of at least one parent carrying A allele in arterial septal defect subgroup (43.48%) was significantly lower than that in controls (69.64%) (P=0.017), with OR=0.34 (95% CI: 0.12-0.92). The analysis of genetic transmission indicated that there was no transmission disequillibrium in CHD nuclear families. Their serum folic acid level was significantly higher than that of controls (P=0.000), and Hcy level of the former was higher than that of the latter with no statistical significance (P>0.05). Serum Hcy and folic acid levels of mothers with gene mutation were lower than those of mothers with no mutation.
Conclusion:
No significant difference of genotype distribution and allele frequency existed between CHD patients and healthy population. MTHFD G1958A mutation in parents (particularly in mother) can decrease the risk of arterial septal defect in offspring. The possible mechanism of protection might be mutation, which can increase MTHFD enzyme activity, folic acid metabolism and homocysteine remethylation, and decrease Hcy level.
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