Relationship between polymorphism of methylenetetrahydrofolate dehydrogenase and congenital heart defect.

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.

[Study of serum Hcy and polymorphisms of Hcy metabolic enzymes in 192 families affected by congenital heart disease].

OBJECTIVE: To explore genotype distributions at MTHFR C677T, MS A2756G, MTHFD G1958A and CBS 844 ins68bp loci in healthy Chinese living in northern area, and to assess the association of single or combined gene mutations with folic acid, Vit.B(12), Hcy levels and CHD. METHODS: 192 patients having CHD and their biological parents in Liaoning province registered as birth defects were included in this study as case group, and 124 healthy subjects (age and gender matched) and their biological parents were simultaneously selected from the same geographic area as control. To all subjects, the gene polymorphism at MTHFR C677T, MS A2756G, MTHFD G1958A and CBS 844 ins68bp loci was examined with PCR-RFLP. The serum folic acid and homocysteine (Hcy) level were analyzed with Radioimmunoassay or fluorescence polarization immunoassay (FPIA). RESULTS: In healthy Chinese living in northern China, the mutant allele frequencies of these four loci were MTHFR 51.18%, MS 7.58%, MTHFD 24.32%, and CBS insertion 2.36%, respectively. The heterozygosity of CBS 844 ins68bp was more prevalent in case than in control (12.57% vs 2.97% in children, 10.88% vs 3.09% in father and 11.54% vs 1.02% in mother, respectively), and yielded an odds ratio (OR) of 4.70 (95% CI 1.34-25.15) in children, 3.83 (95% CI 1.05-20.98) in fathers and 12.65 (95% CI 1.92-532.47) in mothers. There is no existed significant difference at the other three loci. The percents of mothers with MTHFR, CBS and MTHFD gene polymorphisms, of mothers with MTHFR and CBS being polymorphisms (OR=8.44, 95aCI 1.23-362.26), of mothers with MTHFD and CBS being polymorphisms in case were higher than those in control. Serum folic acid levels of mothers and fathers in case were significantly higher than those of counterparts in control. Serum Hcy level of mothers in case was higher than that of counterparts in control without significant difference. Homozygous mutation at MTHFR and MTHFD loci made serum folic acid and Vit.B(12) levels slightly decreased and serum Hcy level increased. CONCLUSION: The study showed presence of ethnic and district difference of gene polymorphisms at these four loci. 68 bp insertion at exon 8 of CBS gene base 844 could be a risk factor for CHD, and the insertion in parents (especially in mothers) could increase CHD risk in offspring.

[Relations between serum homocysteine and folic acid levels with congenital heart disease].

OBJECTIVE: To investigate the relations between serum homocysteine (Hcy) and folic acid with congenital heart disease (CHD) in CHD nuclear families. METHODS: In Liaoning Province 151 CHD patients and their biological parents were selected as the case group, with another 98 normal subjects and their parents as control. For some filial individuals and their mothers the serum total Hcy (tHcy) levels were detected by fluorescence polarization immunoassay. And for all members the serum levels of folic acid and vitamin B12 (VB12) were determined by radio-immunoassay. RESULTS: There were not significantly differences in the serum tHcy and folic acid levels and theirs abnormality prevalence between CHD patients and the control, neither were their parents in the study. Compared with the control group the serum VB12 levels of CHD patients were apparently higher (315.36 pmol/L and 185.34 pmol/L, P < 0.05), and the VB12 deficiency prevalence of patients and their fathers were lower. Analysis of different CHD types showed that in ventricular septal defect patients the serum tHcy levels were lower than the control with VB12 levels higher, and in parents of patent ductus arteriosus patients the serum folic acid levels were increased (P < 0.05). The study also indicated that the folic acid and VB12 of parents were significantly positively associated with that of filial generation. In the case group the tHcy levels of mothers were positively correlated with filial generation, and in CHD patients the tHcy was negatively associated with folic acid. In filial individuals of the control group the tHcy was negatively related with VB12 (P < 0.05). CONCLUSION: Folic acid and VB12 were important influencing factors of serum Hcy and they were negatively correlated. In this study, the folic acid and Hcy were not significantly related with CHD, and it needs further investigations to confirm it. There were not significant differences in the serum tHcy and folic acid levels and theirs abnormality prevalence between CHD patients and the control, neither were their parents in the study. Compared with the control group the serum VB12 levels of CHD patients were apparently higher (315.36 pmol/L and 185.34 pmol/L, P < 0.05), and the VB12 deficiency prevalence of patients and their fathers were lower. Analysis of different CHD types showed that in ventricular septal defect patients the serum tHcy levels were lower than the control with VB12 levels higher, and in parents of patent ductus arteriosus patients the serum folic acid levels were increased (P < 0.05). The study also indicated that the folic acid and VB12 of parents were significantly positively associated with that of filial generation. In the case group the tHcy levels of mothers were positively correlated with filial generation, and in CHD patients the tHcy was negatively associated with folic acid. In filial individuals of the control group the tHcy was negatively related with VB12 (P < 0.05). CONCLUSION: Folic acid and VB12 were important influencing factors of serum Hcy and they were negatively correlated. In this study, the folic acid and Hcy were not significantly related with CHD, and it needsfurther investigations to confirm it.

Polymorphism of methionine synthase gene in nuclear families of congenital heart disease.

OBJECTIVE: To investigate the relation of methionine synthase (MS) gene variation with congenital heart disease (CHD) phenotype. METHODS: One hundred and ninety three CHD patients (94 males and 99 females) and their biological parents (nuclear families) in Liaoning Province were selected as the case group, and another 104 normal persons (60 males and 44 females) and their parents without family history of birth defects as the control group. For all subjects the polymorphism of MS gene A2756G locus was examined by PCR-RFLP method. RESULTS: In offspring of the control group the frequencies of MS genotype (+/-) and allele (+) were 10.7% and 5.3%, without existence of homozygote. The MS genotype distribution and allele frequencies of CHD patients and their mothers were not significantly different from the control (P > 0.05). The frequency of allele (+) in case fathers (5.0%) was apparently lower than that in the control (9.1%, P = 0.060), and the odds ratio (OR) was 0.53 (95% CI: 0.25-1.09). There was no difference in parents' genotype combination between the two groups, and in genotype distribution among different types of CHD. Analysis of genetic transmission indicated that mutation allele (+) existed transmission disequilibrium in CHD nuclear families. The percentage of allele (+) transmitted from parents was lower than that allele (-) with OR 0.26 (95% CI: 0.11-0.60). CONCLUSION: MS gene variation in parents is associated with occurrence of CHD in offspring, and mutation allele (+) in parents may be related with the decrease of CHD risk in offspring.

[Effects of methionine synthase gene variation in parents on occurence of congenital heart disease in offspring].

OBJECTIVE: To investigate the relations of methionine synthase (MS) gene variation in parents with congenital heart disease (CHD) phenotype in offspring. METHODS: We selected 192 CHD patients (93 males and 99 females) and their biological parents (nuclear families) in Liaoning Province as case group, and 104 normal people (60 males and 44 females) and their parents without family history of birth defects as control group. For all subjects the MS gene A2756G locus polymorphism was examined by PCR-RFLP method. The data were analyzed to compare the difference of gene variation between the case parents and controls, and to assess the genetic disequilibrium in the CHD nuclear families. RESULTS: The MS genotype distribution and allele frequencies of the case mothers were not different significantly from those of the control group (P>0.05). The frequency of allele (+) in the case fathers (5.0%) was lower than that of the control (9.1%, P=0.060). The odds ratio (OR) was 0.53 (95% CI: 0.25-1.09). There was no difference in parents' genotype combination between the two groups. The analysis of allele transmission indicated that mutation allele (+) transmission disequilibrium existed in CHD nuclear families. The percentage of allele (+) transmitted from the parents was lower than (-) with being OR 0.26 (95% CI: 0.11-0.60). CONCLUSION: The study shows that the MS gene variation at A2756G locus in parents is associated with occurrence of CHD in offspring, and the mutation allele (+) in parents might be related with the decrease of CHD risk in offspring.