A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs.     

Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil

BACKGROUND: The importance of metabolic factors in neural tube defects (NTDs) has been the focus of many investigations. Several authors have suggested that abnormalities in homocysteine metabolism, such as hyperhomocysteinemia, folate deficiency, and low vitamin B12, may be responsible for these malformations and that both nutritional factors and genetic abnormalities are associated with them. METHODS: We conducted a case-control study to investigate the influence of biochemical and genetic factors in NTDs in infants in southern Brazil. Levels of folate, vitamin B12, total homocysteine (t-Hcy) and the 677C>T and 1298A>C polymorphisms of the MTHFR gene were analyzed in 41 NTD child-mother pairs and 44 normal child-mother control pairs. RESULTS: Subjects in the case group had a higher mean blood folate level than those in the control group. The level of vitamin B12 was lower in mothers in the NTD group than in control mothers (p = 0.004). The level of t-Hcy was not different in the two groups, but t-Hcy and vitamin B12 were correlated (p = 0.002). There was no difference in the genotype distribution for 677C>T and 1298A>C polymorphisms of MTHFR in the case and control pairs. The level of t-Hcy was correlated with 677TT. CONCLUSIONS: Despite the small sample in this study, we suggest that low vitamin B12 and, consequently, hyperhomocysteinemia are important risk factors for NTDs in our population.     

Folate, homocysteine and neural tube defects: an overview

Folate administration substantially reduces the risk on neural tube detects (NTD). The interest for studying a disturbed homocysteine (Hcy) metabolism in relation to NTD was raised by the observation of elevated blood Hcy levels in mothers of a NTD child. This observation resulted in the examination of enzymes involved in the folate-dependent Hcy metabolism. Thus far, this has led to the identification of the first and likely a second genetic risk factor for NTD. The C677T and A1298C mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with an increased risk of NTD and cause elevated Hcy concentrations. These levels can be normalized by additional folate intake. Thus, a dysfunctional MTHFR partly explains the observed elevated Hcy levels in women with NTD pregnancies and also, in part, the protective effect of folate on NTD. Although the MTHFR polymorphisms are only moderate risk factors, population-wide they may account for an important part of the observed NTD prevalence.     

Folate status and neural tube defects

Periconceptional folic acid supplementation prevents approximately 70% of neural tube defects (NTDs). While most women carrying affected fetuses do not have deficient blood folate levels, the risk of having an NTD affected child is inversely correlated with pregnancy red cell folate levels. Current research is focused on the discovery of genetic abnormalities in folate related enzymes which might explain the role of folate in NTD prevention. The first candidate gene to emerge was the C677T variant of 5,10-methylenetetrahydrofolate reductase. Normal subjects who are homozygous for the mutation (TT) have red cell folate status some 20% lower than expected. It is now established that the prevalence of the TT genotype is significantly higher among spina bifida cases and their parents. Nevertheless, our studies show that the variant does not account for the reduced blood folate levels in many NTD affected mothers. We conclude that low maternal folate status may in itself be the most important risk factor for NTDs and that food fortification may be the only population strategy of benefit in the effort to eliminate NTDs.     

Screening of the C677T mutation on the methylenetetrahydrofolate reductase gene in French patients with neural tube defects

We report the analysis of the distribution of the C677T mutation on the methylenetetrahydrofolate reductase (MTHFR) gene in prenatally diagnosed neural tube defects (NTD) cases and controls. In contrast to previous reports, we found the same distribution in fetuses with NTD and controls, which suggests that the MTHFR C677T mutation cannot be regarded as a genetic risk factor for NTD. Received: 23 April 1997 / Accepted: 28 May 1997     

Mutation incidence in folate metabolism genes and regulatory genes in Polish families with neural tube defects

Neural tube defects (NTDs) are a common cause of disability or death of new-borns, but the aetiology and genetic background of this disease are still poorly understood. Therefore, it was decided to determine the conditions for the identification of several polymorphisms and to perform a preliminary study on Polish NTD patients and their parents. According to the results of this study, the genetic predisposition to NTD can be correlated with the 677TT genotype in the MTHFR gene, 677CT/1298AC haplotype (the MTHFR gene), 2756G allele in the MTR gene, 66AG variant and minisatellite sequence with 5 or 10 repeats in intron 6 of the MTRR gene. The 530GG and TIVS7-2/TIVS7-2 genotypes in the T gene could also be considered as a risk factor for NTD. The analysis also revealed no correlation between neurulation disturbances and A4956G and A1186G mutations in the BRCA1 gene and the 844ins68bp in CBS gene. Although a correlation was found of some molecular markers with NTD, an additional examination should be conducted on more numerous groups to obtain statistically significant results.     

Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population

Methylenetetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, C677T and A1298C have been associated with several diseases, including cancer. We made a case-control study to analyze a possible association of MTHFR gene polymorphisms C677T and A1298C with risk for colorectal cancer in an eastern Chinese Han population of 137 patients with a confirmed histopathological diagnosis of CRC and 145 age- and gender-matched controls with no history of cancer. DNA was isolated from peripheral blood samples and the genotypes were determined by PCR-RFLP. The concentrations of folate in plasma were measured by chemiluminescence immunoassay. The MTHFR 677TT genotype had a protective effect against colorectal cancer, with an odds ratio (OR) = 0.467 (95% confidence interval (CI) = 0.225-0.966). The 1298CC genotype was significantly correlated with a reduced risk of colorectal cancer (OR = 0.192; 95%CI = 0.040-0.916). Compared with the MTHFR 677CC and MTHFR 1298 AA genotypes, for individuals who carried both MTHFR 677CC and 1298CC genotypes, the OR of colorectal cancer was 0.103 (95%CI = 0.012-0.900); among individuals who carried both MTHFR 677TT and 1298AC genotypes, the OR for risk of colorectal cancer was 0.169 (95%CI = 0.044-0.654). MTHFR 677TT+CT genotypes had a significantly lower plasma folate concentration than those with the MTHFR 677CC genotype. MTHFR 1298AC+CC genotypes had a lower plasma folate concentration than those with the MTHFR 1298AA genotype (P < 0.05). In conclusion, subjects with the MTHFR 677TT and MTHFR 1298CC genotypes appeared to have a significantly lower risk for colorectal cancer. MTHFR haplotypes 677CC/1298CC and 677TT/1298AC were less common in cases than in controls. These haplotypes, when compared to the most common haplotype 677CC/1298AA, were associated with a decreased risk for colorectal cancer. We conclude that plasma folate level is influenced by MTHFR genotypes.     

Frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene at the early stage of human individual development

In most cases, the cause of embryo and fetus death remains unclear although the multifactorial causes are suspected. The polymorphic C677T and A1298C variants of the MTHFR gene are associated with an increase in the level of homocysteine, which is risk factor of pregnancy loss. The subject of this study is analysis of genotypes and haplotypes of C677T and A1298C polymorphic variants of MTHFR genes in the groups of spontaneous abortions with the normal karyotype and newborns in the Tomsk population. Between these groups, no statistically significant differences were determined in the allele, genotype, and haplotype distributions of C677T and A1298C polymorphisms of the MTHFR gene. The haplotype frequencies of C677T and A1298C polymorphic variants of MTHFR gene in the Russian populations, which proved to be similar to those in most European populations, are presented.     

Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C→T and 1298 A→C, have been shown to impact various diseases, including cancer. The 677 C→T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population.     

5,10‐Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms: genotype frequency and association with homocysteine and folate levels in middle‐southern Italian adults.

Two genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) can influence the plasma homocysteine (Hcy) levels, especially in the presence of an inadequate folate status. The aim of this study was to evaluate the frequencies of C677T and of A1298C MTHFR polymorphisms and their correlation with Hcy and serum folate concentrations in a population of blood donors living in a region of middle‐southern Italy (the Molise Region). One hundred ninety seven blood donors were studied for total plasma Hcy, serum folate and C677T and A1298C MTHFR genotypes. The frequency of C677T genotypes was 20.8% (CC), 49.8% (CT) and 29.4% (TT); for the A1298C genotypes: 48.7% (AA), 43.7% (AC) and 7.6% (CC). Hcy and serum folate concentrations were significantly different among genotypes of the C677T polymorphism (CC versus CT versus TT: <0.0001 both for Hcy and folate), with Hcy values increasing, and serum folate decreasing, from CC to TT subjects. Regarding to A1298C polymorphism, the difference among genotypes (AA versus AC versus CC; p: 0.026 for Hcy and 0.014 for serum folate), showed an opposite trend for both parameters, with Hcy higher in the wild‐type and lower in the homozygotes and serum folate higher in CC than in AA subjects. In conclusion, we found a high frequency of MTHFR allele associated with high level of Hcy and low levels of folate in an Italian southern population. Copyright © 2013 John Wiley & Sons, Ltd.     

Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies

Background

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs.

Methods

An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis.

Results

A significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR  = 2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR  = 1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR  = 1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR  = 1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls.

Conclusion

The results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted.     

The C677T polymorphism of the methylenetetrahydrofolate reductase gene in Mexican mestizo neural-tube defect parents, control mestizo and native populations

The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene, associated with the thermolabile form of the enzyme, has reportedly been found to be increased in neural-tube defects (NTD), though this association is still unclear. A group of 107 mestizo parents of NTD children and five control populations: 101 mestizo (M), 50 Huichol (H), 38 Tarahumara (T), 21 Purepecha (P) and 20 Caucasian (C) individuals were typed for the MTHFR C677T variant by the PCR/RFLP (HinfI) method. Genotype frequencies were in agreement with the Hardy-Weinberg expectations in all six populations. Allele frequency (%) of the C677T variant was 45 in NTD, 44 in M, 56 in H, 36 in T, 57 in P, 35 in C. Pairwise inter-population comparisons of allele frequency disclosed a very similar distribution between NTD and M groups (exact test, P=0.92). Among controls, differences between M and individual native groups were NS (0.06相似文献   

Rate of T alleles and TT genotype at MTHFR 677C‐>T locus or C alleles and CC genotype at MTHFR 1298A‐>C locus among healthy subjects in Turkey: impact on homocysteine and folic acid status and reference intervals

Methylenetetrahydrofolate reductase (MTHFR) is important for folate and homocysteine (Hcy) metabolism. MTHFR 677C‐>T and 1298A‐>C MTHFR are two most common mutations which can affect folate and total homocysteine (tHcy) status. This study was designed to determine the rate of MTHFR 677C‐>T and 1298A‐>C mutations, and their influence on serum folate, Hcy and vitamin B12 status and the reference intervals in 402 healthy Turkish adults. The rate of MTHFR 677C‐>T or 1298A‐>C mutations was 50.7% or 54.7%, respectively. The MTHFR 677C‐>T mutation‐specific reference intervals for serum folate and tHcy were characterized by marked shifts in their upper limits. In homozygote subjects for MTHFR 677C‐>T serum folate concentration was lower and serum tHcy concentration was higher than those in the wild genotype; all subjects had lower serum folate and 54% of the subjects had higher tHcy concentrations than the cutoff values of ≤10 nmol/L and ≥12 µmol/L, respectively. Serum vitamin B12 status was similar in all genotypes. Serum tHcy concentrations were inversely correlated with serum folate and vitamin B12 concentrations in all genotypes. These data show that the rate of MTHFR 677C‐>T and 1298A‐>C mutations is very high in Turks and serum folate and tHcy status are impaired by these mutations. Copyright © 2009 John Wiley & Sons, Ltd.     

Two MTHFR polymorphisms, maternal B-vitamin intake, and CHDs

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with complex congenital malformations. Whether these polymorphisms are associated with CHDs is not clear. We studied both MTHFR polymorphisms, folate and vitamin B2 by maternal food intake and supplements, and CHD risk. METHODS: A case‐control family study was conducted in a European population in the Netherlands including 230 case and 251 control children with both parents. Approximately 17 months after the index pregnancy, mothers filled out standardized questionnaires on periconception use of folic acid supplements and a validated food frequency questionnaire on current dietary folate and vitamin B2 intake. All subjects were genotyped for the MTHFR C677T and A1298C polymorphisms. Data were analyzed by logistic regression analysis and ORs and 95% CIs were calculated. For the interaction analysis the dominant model was used. RESULTS: The risk estimates for the MTHFR 677 CT genotypes were 1.4 (0.9–2.0) in mothers, 1.1 (0.8–1.6) in fathers, and 1.2 (0.8–1.7) in children, and for the MTHFR 677 TT genotypes 0.9 (0.6–1.2), 1.4 (1.0–1.9), and 1.0 (0.7–1.3), respectively. The MTHFR 1298 CC genotype in fathers and the MTHFR 1298 AC genotype in children significantly reduced CHD risk, 0.6 (0.5–0.9) and 0.6 (0.4–0.9), respectively. Of interest is the significant interaction (p = .008) towards a nearly twofold increased risk in mothers carrying the MTHFR 1298C allele and using a periconception folic acid supplement. CONCLUSIONS: The MTHFR C677T and A1298C polymorphisms are not strong risk factors for CHDs. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Polymorphisms of 5,10-methylenetetralydrofolate reductase (MTHFR), fruit and vegetable intake, and the risk of stomach cancer

Stomach cancer is a serious public health problem in China. 5,10-Methylenetetralydrofolate reductase (MTHFR) may be involved in both DNA methylation and DNA synthesis. Folate deficiency is associated with cancer risk that may be modulated by a genetic variation in the MTHFR gene in folate metabolism. The main goal of this study was to evaluate the association between polymorphisms of the MTHFR gene and the risk of stomach cancer. This study also explored the modification effects of fruit and vegetable intake (one of the main constituents is folate) on the risk of this disease. A population-based case-control study was conducted in Taixing, China, consisting of 206 newly diagnosed cases with primary stomach cancer and 415 healthy population controls. Polymorphisms of MTHFR C677T and A1298C were assayed by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) techniques. The data were analysed using the logistic regression model. No obvious association between the MTHFR A1298C polymorphism and the risk of stomach cancer was observed in this study. The frequencies of 677 C/C, C/T, and T/T were 34.5, 50.9, and 14.6%, respectively, in controls. The frequency of the MTHFR 677 wild homozygotic genotype was 25.8% in cases, which was lower than that in controls (34.5%). The adjusted odds ratio (OR) for the MTHFR 677 any T genotype was 2.05 (95% confidence interval (CI), 1.26-3.34) when compared with the C/C genotype. In the low fruit and vegetable intake group an increasing trend was observed with the T allele exposure, p=0.0056. The adjusted ORs were 1.68 (95% CI = 0.86-3.29) for the C/T genotype and 3.58 (95% CI = 1.46-8.75) for the T/T genotype, respectively. The MTHFR 677 any T genotype was associated with an increased risk of primary stomach cancer among the Chinese population. Folate deficiency might modify the MTHFR gene polymorphism and influence the risk of stomach cancer.     

MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians

The goals of our present study were to measure plasma homocysteine levels and determine their association with methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) in essential hypertensive subjects. Plasma total homocysteine and folic acid levels were measured in essential hypertensive patients (n = 153) before and after oral supplementation with either 5 mg folic acid tablet/day or 5 mg placebo/day for 4 weeks and compared with age and sex matched normotensive controls (n = 133). MTHFR gene polymorphisms (C677T and A1298C) were studied by restriction fragment length polymorphism and correlated with plasma homocysteine levels. Homocysteine levels were significantly higher in hypertensive patients as compared to controls and showed a negative correlation with plasma folate levels. Folic acid supplementation (5 mg/day) for 4 weeks resulted in a significant decrease in plasma homocysteine concentrations in these patients. Patients carrying MTHFR 677T allele (OR = 1.90; 95%CI: 1.14–3.19) or MTHFR 1298C (OR = 2.6, 95%CI: 1.55–4.40) allele were at increased risk of hypertension. The frequency of co-occurrence of MTHFR 677 CT/1298 CC genotypes was significantly higher in the patients compared to controls (P < 0.05) and was associated with increased risk of hypertension (OR = 3.54, 95%CI: 0.37–4.30). Subjects with MTHFR 1298 CC genotype had significantly higher homocysteine levels compared to those with MTHFR 1298 AA genotype (P < 0.05). Our results indicate that MTHFR 677T and 1298C alleles and co-occurrence of MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension and MTHFR 1298 CC genotype is associated with higher homocysteine levels in our subjects.     

Functional inference of the methylenetetrahydrofolate reductase 677 C > T and 1298A > C polymorphisms from a large-scale epidemiological study

Two functional single nucleotide polymorphisms, 677C > T and 1298A > C have been described for the methylenetetrahydrofolate (MTHFR) gene. Both are associated with reduced enzyme activity in vitro. For the 677T, but not the 1298C allele, significantly lower serum folate and higher plasma total homocysteine (tHcy) have been reported. We genotyped 10,034 middle-aged (50–64 years old) subjects and measured serum folate and tHcy. Within strata of 677 genotypes, 1,298 genotypes had significantly different serum folate and tHcy (P ≤ 0.03 for all comparisons). Each additional 1298C allele reduced mean serum folate and increased mean tHcy, by (on average) 4.5 and 3.0%, respectively. In comparison, within strata of 1,298 genotypes, the increase from no, to one 677T-allele reduced serum folate and increased tHcy by, 7.1 and 6.3%, respectively. Lowest serum folate and highest tHcy level was found for the 677TT/1298AA genotype. The difference in tHcy was significantly larger at low folate than at high folate when genotypes 677TT/1298AA and 677CT/1298AA, 677CT/1298AC and 677CC/1298AC, and genotypes 677CT/1298AC and 677CT/1298AA were compared. We interpreted these data in the context of a model of the MTHFR enzyme that describes the enzyme as a dimer that mainly exist in six different configurations. The model reconciled the observed phenotypic effects of the 677/1,298 combination genotypes with previous in vitro measurements, and identified enzyme configurations that are sensitive to low folate levels. In conclusion, this report demonstrates functional inference of the MTHFR 677 C > T and 1,298 A > C polymorphisms from a large-scale epidemiological study.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and nonsyndromic orofacial clefts susceptibility in a southern Chinese population

Nonsyndromic orofacial clefts (NSOC) are one of the most common congenital anomalies in humans. Great efforts have been taken to unravel its genetic background. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme in folate metabolism and two of its functional polymorphisms, MTHFR C677T and MTHFR A1298C, might be associated with NSOC susceptibility. The aim of the present study was to investigate their associations with risks of NSOC in a southern Chinese population. We found that MTHFR 677 TT and 677 CT/TT were associated with increased risk of cleft lip with or without cleft palate; meanwhile, MTHFR 1298 AC and 1298 AC/CC had protective effects against cleft lip with or without cleft palate. In further stratified analysis, we found that MTHFR 677 CT contributed to elevated risk of cleft lip only, as did MTHFR 677 CT/TT. On the contrary, MTHFR 1298 AC and 1298 AC/CC appeared to be protective against cleft lip with cleft palate. These results suggested that these two polymorphisms were involved in the development of NSOC in a southern Han Chinese population.     

Genetic Association Analyses of Nitric Oxide Synthase Genes and Neural Tube Defects Vary by Phenotype

Neural tube defects (NTDs) are caused by improper neural tube closure during the early stages of embryonic development. NTDs are hypothesized to have a complex genetic origin and numerous candidate genes have been proposed. The nitric oxide synthase 3 (NOS3) G594T polymorphism has been implicated in risk for spina bifida, and interactions between that single nucleotide polymorphism (SNP) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have also been observed. To evaluate other genetic variation in the NO pathway in the development of NTDs, we examined all three NOS genes: NOS1, NOS2, and NOS3. Using 3109 Caucasian samples in 745 families, we evaluated association in the overall dataset and within specific phenotypic subsets. Haplotype tagging SNPs in the NOS genes were tested for genetic association with NTD subtypes, both for main effects as well as for the presence of interactions with the MTHFR C677T polymorphism. Nominal main effect associations were found with all subtypes, across all three NOS genes, and interactions were observed between SNPs in all three NOS genes and MTHFR C677T. Unlike the previous report, the most significant associations in our dataset were with cranial subtypes and the AG genotype of rs4795067 in NOS2 (p = 0.0014) and the interaction between the rs9658490 G allele in NOS1 and MTHFR 677TT genotype (p = 0.0014). Our data extend the previous findings by implicating a role for all three NOS genes, independently and through interactions with MTHFR, in risk not only for spina bifida, but all NTD subtypes.     

Neural tube defects, methylenetetrahydrofolate reductase mutation, and north/south dietary differences in China

There is a well-recognized correlation between methylenetetrahydrofolate reductase (MTHFR) C677T mutation homozygosity, elevated plasma homocysteine, and increased risk of neural tube defects (NTDs). This risk is modulated by maternal and fetal folate levels provided provided by diet or supplement. Although the frequencies of the C677T mutation are nearly identical between north and south China, the incidence of NTDs is nearly 5 times greater in the north than in the south. This dramatic difference appears related to the fact that dietary sources of folate are more plentiful and varied in South China.