Methylenetetrahydrofolate Reductase Genetic Polymorphisms Research Articles

Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review

The authors performed a meta-analysis of studies examining the association between polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, including MTHFR C677T and A1298C, and common psychiatric disorders, including unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia. The primary comparison was between homozygote variants and the wild type for MTHFR C677T and A1298C. For unipolar depression and the MTHFR C677T polymorphism, the fixed-effects odds ratio for homozygote variants (TT) versus the wild type (CC) was 1.36 (95% confidence interval (CI): 1.11, 1.67), with no residual between-study heterogeneity (I(2) = 0%)--based on 1,280 cases and 10,429 controls. For schizophrenia and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.44 (95% CI: 1.21, 1.70), with low heterogeneity (I(2) = 42%)--based on 2,762 cases and 3,363 controls. For bipolar disorder and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.82 (95% CI: 1.22, 2.70), with low heterogeneity (I(2) = 42%)-based on 550 cases and 1,098 controls. These results were robust to various sensitively analyses. This meta-analysis demonstrates an association between the MTHFR C677T variant and depression, schizophrenia, and bipolar disorder, raising the possibility of the use of folate in treatment and prevention.

Role of MTHFR polymorphisms and folate levels in different phenotypes of sporadic colorectal cancers

By altering both DNA methylation and nucleotide synthesis, folate metabolism is thought to contribute to colorectal carcinogenesis. We examined the role of folate metabolism in three different phenotypes of sporadic colorectal cancers (CRCs), phenotypes that were classified by the status of microsatellite instability (MSI) and chromosomal instability (CIN): MSI-H, microsatellite stability (MSS)/aneuploidy, and MSS/diploid. A total of 195 sporadic colorectal tumors and another 195 age- and gender-matched healthy volunteers in Taipei-Veteran General Hospital and Taipei City Hospital were collected. We analyzed for MTHFR (methylenetetrahydrofolate reductase) polymorphisms (C677T, A1297C), folate, and vitamin B(12) levels. We determined MSI status and DNA ploidy with fluorescent polymerase chain reaction and flow cytometry. Relations between clinicopathological variables and molecular variables were analyzed by chi (2) tests (with Yates' correction) for categorical variables and Student's t test for numerical variables. Folate levels (5.02+/-4.43 ng/ml) were significantly lower in cancer patients than in controls (7.22+/-4.46 ng/ml). Vitamin B(12) level was similar between cancer patients and controls. The frequency of the TT genotype of MTHFR C627T (12.3%) was slightly higher than controls (8.2%), but it did not reach statistical significance (p=0.174). Within the low-folate group (<5 ng/ml), the frequency of the TT genotype in cancer patients (14.4%) was significantly higher than in controls (4.6%). Sixteen patients who had MSI-H CRC (8.2%) had a significantly higher frequency of TT MTHFR (37.5%) and lower folate levels (3.56+/-2.41 ng/ml) than patients with MSS tumors (10.1%, 5.14+/-3.72 ng/ml). Patients with MSS/aneuploid tumors had significantly lower folate levels (4.50+/-3.06 ng/ml) than those with MSS/diploid tumors (6.69+/-4.73 ng/ml). Folate deficiency and the MTHFR genetic polymorphism play an important role in colorectal carcinogenesis, including MSI and CI. Folate metabolism plays an important role in colorectal carcinogenesis. We demonstrate that patients with MSI-H tumors had higher frequency of TT MTHFR C627T (37.5%), and patients with MSS/aneuploid tumor had lower folate level (4.50+/-3.06 ng/ml).

Genetic polymorphisms of methylenetetrahydrofolate reductase and colorectal cancer and adenoma

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA methylation and synthesis. Two functional, common polymorphisms (C677T and A1298C) are known in the MTHFR gene. MTHFR activity is lowered in individuals with the 677TT genotype and is somewhat reduced in those with the 1298CC genotype. We reviewed the consistency of reported associations of these polymorphisms with colorectal cancer and adenoma with consideration of the effects of nutritional status. A total of 16 studies have addressed the association between MTHFR C677T polymorphism and colorectal cancer in 10 countries. Decreased risk of colorectal cancer associated with the 677TT genotype has fairly consistently been observed, with few exceptions. This decrease was observable in people with either high or low folate status. Alteration in the thymidylate pool associated with MTHFR activity is postulated as an underlying mechanism. Studies on the A1298C polymorphism are limited, and their results are variable. Almost all of seven studies of colorectal adenoma have found no association between C677T polymorphism and adenoma, but the 677TT genotype seems to be related to increased risk when folate status is poor. Reduced availability of methyl groups for DNA methylation might be more relevant to adenoma formation. Although the underlying mechanisms still remain to be clarified, epidemiological findings regarding MTHFR C677T polymorphism provide strong evidence that adequate folate status confers protection from colorectal cancer.

Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase and Risk of Pancreatic Cancer

Human pancreatic cancer might be associated with folate deficiency and impaired metabolism. We tested this hypothesis by examining the contribution of functional polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) to risk of cancer. DNA from 163 pancreatic cancer patients and 337 control subjects was genotyped for MTHFR (677C > T and 1298A > C) and TS (5'-untranslated region tandem repeat and G/C). Association with risk of pancreatic cancer was estimated by logistic regression. All statistical tests were two-sided. We observed an increased risk of pancreatic cancer associated with the MTHFR 677CT (odds ratio [OR], 2.60; 95% confidence interval [CI], 1.61-4.29; P = .0005) or 677TT (OR, 5.12; 95% CI, 2.94-9.10; P < .0001) genotype compared with the MTHFR CC genotype. An increased risk of pancreatic cancer was also associated with the TS 3Rc/3Rc genotype (OR, 2.19, 95% CI, 1.13-4.31; P = .022) compared with the TS 3Rg/3Rg genotype. Joint effect between MTHFR C677T polymorphism and smoking or drinking increased risk of pancreatic cancer in a super-multiplicative manner. The ORs for smoking, the polymorphism, and both factors combined were 0.70 (95% CI, 0.30-1.63), 2.17 (95% CI, 1.17-4.21), and 3.10 (95% CI, 1.54-6.51), respectively. This joint effect was much stronger in heavy smokers (OR, 6.69; 95% CI, 3.39-13.63; P < .0001). The ORs for drinking, the polymorphism, and both factors combined were 0.98 (95% CI, 0.40-2.30), 2.81 (95% CI, 1.65-4.98), and 4.39 (95% CI, 2.25-8.78), respectively. The MTHFR and TS polymorphisms are genetic determinants for developing pancreatic cancer.

Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self‐Defense Forces Health Study

Methylenetetrahydrofolate reductase is a key enzyme in folate metabolism, which affects DNA synthesis and methylation and is possibly linked to colorectal carcinogenesis. Alcohol and acetaldehyde have an adverse effect on folate metabolism. This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals. The study subjects were 452 cases of colorectal adenoma and 1050 controls with no polyp who underwent total colonoscopy. Genotypes were determined by the PCR-RFLP method using genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index, cigarette-years and alcohol intake. Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma. While high alcohol consumption was associated with a moderately increased risk of colorectal adenoma, neither of the two polymorphisms showed a significant effect on the association between alcohol and colorectal adenoma. Individuals with the variant alleles ALDH2*2 and MTHFR 677T had a decreased risk of colorectal adenomas, showing adjusted odds ratios of 0.70 (95% confidence interval 0.49-1.00) for all adenomas and 0.57 (0.34-0.95) for large adenomas (> or = 5 mm), as compared to individuals with ALDH2*1/1 and MTHFR 677CC genotypes combined. The findings may be interpreted as suggesting that folate inhibits the growth of colorectal adenomas, but further confirmation is needed.

A Novel Single Nucleotide Polymorphism of the Human Methylenetetrahydrofolate Reductase Gene in Japanese Individuals

The genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) have been associated with increased toxicity of methotrexate (MTX), a folic acid antagonist that is widely used to treat cancer and immunosuppressive disorders such as rheumatoid arthritis. In this study, we analyzed all the exons and exon/intron junctions of the MTHFR gene from 200 Japanese individuals. We detected a novel single nucleotide polymorphism (SNP) 148C>T (Arg46Trp) in exon 1. The allele frequency of this polymorphism in the Japanese population appears to be extremely low (0.25%).

Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia

AbstractThe central role of methylenetetrahydrofolate reductase (MTHFR) in the folate metabolism renders MTHFR gene polymorphisms (C677T and A1298C) potential modulators of a variety of disorders whose development depends on folate/homocysteine imbalance. Here, we provide additional evidence on the protective role of these polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric cancer. A case-control study was conducted in 270 ALL patients and 300 healthy controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298 individuals were associated with reduced risk of ALL (crude odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6; respectively). Further stratification in patients born before and after January 1996 (approximate time of Health Canada recommendation for folic acid supplement in pregnancy) revealed that the protective effect of MTHFR variants is accentuated and present only in children born before 1996. Similar results were obtained when a transmission disequilibrium test was performed on a subset of children (n = 95) in a family-based study. This finding suggests gene-environment interaction and its role in the susceptibility to childhood ALL, which is consistent with previous findings associating either folate deficiency or MTHFR polymorphisms with risk of leukemia.

Genetic polymorphism of methylenetetrahydrofolate reductase as a risk factor for diabetic nephropathy in Chinese type 2 diabetic patients

Objective: Genetic predisposition has been implicated in diabetic nephropathy (DN). The C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene, one of the key enzymes catalyzing remethylation of homocysteine, may play a role in the development of not only vascular disease but also diabetic microangiopathies. In this study, we examined the distribution of the MTHFR genotypes in the Chinese population and the association between the C677T variant and diabetic nephropathy. Methods: 220 unrelated patients with type 2 diabetes mellitus and 130 controls were recruited. The MTHFR genotype was analyzed by PCR followed by HinfI digestion. Plasma total homocysteine levels were measured using high-performance liquid chromatography (HPLC) with fluorescence detection. Results: In 130 healthy control subjects, the frequency of the mutant T allele was 30.0%, comparable to that of a Hong Kong (Chinese) population. The distribution of the three genotypes was as follows: TT genotype, 16.9%; CT genotype, 26.2%; and CC genotype, 56.9%. This genotype distribution did not differ between control subjects and type 2 diabetic patients in which 19.1% were TT, 34.5% were CT and 46.4% were CC (χ2=3.85, P>0.05). The frequency of the mutant T allele was 42.3% in diabetic patients with nephropathy (n=124) versus 28.6% in those without nephropathy (n=96). The genotype frequencies were TT, 21.0%; CT, 42.7%; CC, 36.3% in diabetic patients with nephropathy versus TT, 16.7%; CT, 23.9%; CC, 59.4% in those without nephropathy. The MTHFR genotype and allele frequencies were different between diabetic patients with and without nephropathy (χ2=12.27, P<0.005; χ2=8.77, P<0.005, respectively). Moreover, plasma homocysteine levels were markedly higher in individuals with TT genotype than those with CC or CT genotype. Conclusions: The C677T mutation of MTHFR gene is common in the Chinese population. MTHFR C677T gene polymorphism associated with a predisposition to increased plasma homocysteine levels may represent a genetic risk factor for diabetic nephropathy in Chinese type 2 diabetic patients.

Genotyping of the MTHFR gene polymorphism, C677T in patients with leukemia by melting curve analysis.

Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in folate metabolism and displays common genetic polymorphisms affecting the enzyme activity. The MTHFR genetic polymorphisms have been associated with a decrease in the risk of developing the lymphoid but not myeloid form of pediatric and adult leukemias. In this study we describe the genotyping of the MTHFR C677T polymorphism by melting curve analysis with the LightCycler in a case-controlled study of patients with acute lymphocytic leukemia (ALL), myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), and assess the effect of this common polymorphism on the leukemia risk in adult patients in Turkey. DNA from peripheral blood lymphocytes was used for genotyping in the LightCycler PCR by melting curve analysis. The risk of leukemia associated with the MTHFR polymorphism was evaluated by comparing the genotype frequencies between the control and patient groups. The frequency of the homozygote variant genotype (677TT) was lower than that in healthy individuals in all three leukemia groups. The 677TT genotype did not appear to have a protective effect in patients with ALL (Odds ratio [OR] = 0.78 with a 95% confidence interval [CI] = 0.24-2.59), compared with healthy controls. The difference was higher (4.3-fold) in patients with AML, but still non-significant (OR = 0.23 with a 95% CI = 0.03-1.83). In patients with CML, the frequencies of both heterozygous (677CT) and homozygote variant genotypes were lower (OR = 0.72 and 0.66, respectively). Our results suggest that the MTHFR C677T polymorphism displays a similar distribution pattern in lymphoid and myeloid leukemias and that the frequency of the homozygote variant genotype (677TT) is lower in all leukemia types.

Methionine synthase (MTR) 2756 (A → G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome

Contradictory findings have been recently published on the evaluation of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C-->T) and methionine synthase reductase (MTRR 66 A-->G) as risk factors for having a child with Down syndrome (DS); however, the influence of polymorphisms of methionine synthase (MTR 2756 A-->G) and of MTHFR 1298 A-->C has never been evaluated. In this study, the risk of being a DS case or having a DS child (case mother) was studied by multiple logistic regression analysis of the independent and combined genotypes and of plasma homocysteine, folates, and vitamin B12 in 92 DS cases and 140 control subjects as well as in 63 case mothers and 72 age-matched control mothers from Sicily. (The MTHFR 677 T allele frequency was not different in DS cases and case mothers, compared to the respective control groups). After adjustment for age, total homocysteine (t-Hcys) and MTR 2756 AG/GG genotype were significant risk factors for having a DS child, with odds ratio (OR) of 6.7 (95% CI: 1.4-32.0, P = 0.016) and of 3.5 (95% CI: 1.2-10.9, P = 0.028), respectively. By comparison, MTR 2756 AG/GG genotype increased significantly the risk of being a DS case, with an OR of 3.8 (95% CI: 1.4-10.5, P = 0.009). The double heterozygosity MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a DS child, with an OR estimated at 5.0 (95% CI: 1.1-24.1), after adjustment for t-Hcys. In conclusion, our results provide evidences that homocysteine and MTR genetic polymorphism are two potent risk factors for mothers to have a DS child in Sicily.

Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?

One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C --> T and 1298 A --> C), of methionine synthase (MTR 2756 C --> G), methionine synthase reductase (MTRR 66 A --> G) and transcobalamin (TCN 776 C --> G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C --> T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C --> T and MTRR 66 A --> G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C --> T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations.

Epidemiologic Studies of Folate and Colorectal Neoplasia: a Review

Dietary folate influences DNA methylation, synthesis and repair. Aberrations in these DNA processes may enhance carcinogenesis, particularly in rapidly proliferative tissues such as the colorectal mucosa. DNA methylation abnormalities may influence the expression of cancer-related genes, and inadequate levels of folate may lead to uracil misincorporation into DNA and to chromosomal breaks. Folate deficiency enhances intestinal carcinogenesis in several animal models. An increasing number of epidemiologic studies indicate that higher intakes of folate either from dietary sources or from supplements may lower the risk of colorectal adenoma and cancer. More limited data also suggest that dietary methionine, which might also influence methylation, may have a similar protective role. High alcohol consumption, which has a strong antifolate effect, also has been related to higher risk of colorectal neoplasia. The deleterious effects of alcohol are accentuated when folate or methionine intake is low. Some evidence also suggests that the risk of colorectal neoplasia may vary according to genetic polymorphisms in methylenetetrahydrofolate reductase, an enzyme that is involved in folate metabolism. The cumulative data indicate that maintaining adequate folate levels may be important in lowering risk of colorectal cancer.

Response to “genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A”

Response to “genetic polymorphisms of methylenetetrahydrofolate reductase (<i>MTHFR</i>) and methionine synthase reductase (<i>MTRR</i>) in ethnic populations in Texas; a report of a novel <i>MTHFR</i> polymorphic site, G1793A”

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A.

The importance of hyperhomocysteinemia, birth defects, and vascular diseases has been the subject of intense investigations. The polymorphic MTHFR mutations (C677T and A1298C) cause mild hyperhomocysteinemia, especially in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The subject of this report is the frequency of the polymorphic mutations in the MTHFR gene C677T, C1298A, and newly discovered mutation G1793A, as well as the association with MTRR polymorphic site A66G in different ethnic groups. Four ethnic groups were studied: African-Americans, Caucasians, Hispanics, and Ashkenazi Jews. There are statistically significant differences in the frequency of these alleles in the different populations studied, which impacts compound heterozygosity for such alleles in these populations. DNA samples obtained from the blood of healthy individuals of African-Americans, Hispanics, and Caucasians from south Texas were analyzed and compared to those obtained from Ashkenazi Jewish individuals. The polymorphic site, the G1793A allele, is least frequent among Ashkenazi individuals, 1.3%, compared to 6.9% among Caucasians (P = 0.001), 5.8% among Hispanics (P = 0.012), and 3.1% among African-Americans. The MTRR polymorphic site shows the lowest allele frequency among Hispanics, 28.6%, compared to 34% among African-Americans, 43.1% among Ashkenazi Jews (P = 0.002), and 54.4% among Caucasians (P < 0.0001). Statistically significant differences in allele frequencies of C677T and C1298A polymorphisms were also observed in these populations. Compound heterozygosity for multiple polymorphic alleles may play a role in birth defects and vascular diseases.

Genetic Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR) and Coronary Artery Disease

A high plasma homocysteine concentration is a risk factor for atherosclerotic disease and venous thrombosis. Homocysteine levels are influenced by folic acid, vitamin B 6 and vitamin B 12, as well as by hereditary factors. A common genetic variant of the methylenetetrahydrofolate reductase (MTHFR) gene CC 677 T) is associated with thermolability of the MTHFR enzyme and elevated plasma homocysteine concentration, especially in those with low folic acid concentration. The prevalence of point mutation (nucleotide 677 C → T) in MTHFR was measured in patients with coronary artery disease (CAD) who all underwent coronary artery bypass surgery (62 cases; age 64.0 ± 9.5 years), and was compared with, age-matched control subjects. In patients with coronary artery disease (CAD), we investigated the prevalence of point mutation (nucleotide 677 C → T) in MTHFR in comparison with control subjects. Heterozygous (C/T) prevalence for the 677 C → T mutation in the MTHFR was higher in patients with CAD than in control subjects (P < 0.05). The prevalence of homozygosity (C/C) for wild-type MTHFR was lower in patients with CAD in comparison with control subjects (P < 0.05).

Neonatal and Fetal Methylenetetrahydrofolate Reductase Genetic Polymorphisms: An Examination of C677T and A1298C Mutations

Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy. Folate sufficiency is thought to play an integral role in the phenotypic expression of MTHFR mutations. Samples of neonatal cord blood (n=119) and fetal tissue (n=161) were analyzed for MTHFR C677T and A1298C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis revealed that all possible MTHFR genotype combinations were represented in the fetal group, demonstrating that 677T and 1298C alleles could occur in both cis and trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contain three and four mutant alleles, respectively, were not observed in the neonatal group (P=.0402). This suggests decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This is the first report that describes the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrates their potential role in compromised fetal viability.

Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) and coronary artery disease

Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR) and coronary artery disease

Methylenetetrahydrofolate reductase polymorphism and risk of colorectal adenomas

A homozygous mutation at bp 677 in the gene for the methylenetetrahydrofolate reductase (MTHFR) was previously shown to be associated with a decreased risk of colorectal cancer. We examined the relation between the MTHFR genetic polymorphism and risk of colorectal adenoma in Japanese men using 205 cases of colorectal adenomas and 220 controls of normal total colonoscopy. The homozygous mutation was not measurably associated with colorectal adenomas. The findings corroborate the lack of an association between the MTHFR genotype and colorectal adenomas, but do not deny the possibility that the genotype may be involved in the late stage of colorectal carcinogenesis.

Apolipoprotein E and methylenetetrahydrofolate reductase genetic polymorphisms in relation to other risk factors for cardiovascular disease in UK Caucasians and Black South Africans

Genetic polymorphisms for apolipoprotein E (apo E) and methylenetetrahydrofolate reductase (MTHFR) are believed to modulate risk of coronary heart disease (CHD) acting through regulation of lipid and homocysteine metabolism, respectively. The distributions of apo E and MTHFR alleles in Black South Africans, a population with a low CHD incidence, and UK Caucasians from the Cambridge area, with a higher CHD incidence, were therefore compared. Clinically healthy volunteers (207), including 107 UK Caucasians from the Cambridge area and 100 Black South Africans, participated in the study. Apo E and MTHFR genotypes were determined in all of them. Analyses for serum total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and plasma fibrinogen were carried out in 65 UK Caucasians and 60 Black South Africans. The apo E ε4 allele, which is associated with elevated CHD risk, was present in 48% of Black South Africans compared to 20.8% of Caucasians ( P<0.0001); however, both total and LDL cholesterol levels in Black South Africans were 18–32% lower than in Caucasians with similar apo E genotypes. Hyperhomocysteinemia-causing MTHFR 677T variant was detected in only 20% of Black South Africans (no homozygotes) versus 56% of Caucasians with 12% homozygotes ( P<0.0001). Our findings suggest that the potentially unfavourable pattern of apo E allele distribution in Black South Africans does not result in increased CHD incidence due to protection by dietary and/or other life style related factors. The exceptionally low frequency of MTHFR mutant homozygotes in this population suggests that this polymorphism should not be regarded as an important CHD risk factor among Black South Africans.

Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects

Folic acid administration to women in the periconceptional period reduces the occurrence of neural tube defects (NTDs) in their offspring. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), 677C→12;T, is the first genetic risk factor for NTDs in man identified at the molecular level. The gene encoding another folate-dependent enzyme, methionine synthase (MTR), has recently been cloned and a common variant, 2756A→12;G, has been identified. We assessed genotypes and folate status in 56 patients with spina bifida, 62 mothers of patients, 97 children without NTDs (controls), and 90 mothers of controls, to determine the impact of these factors on NTD risk. Twenty percent of cases and 18% of case mothers were homozygous for the MTHFR polymorphism, compared to 11% of controls and 11% of control mothers, indicating that the mutant genotype conferred an increased risk for NTDs. The risk was further increased if both mother and child had this genotype. The MTR polymorphism was associated with a decreased O.R. (O.R.); none of the cases and only 10% of controls were homozygous for this variant. Red blood cell (RBC) folate was lower in cases and in case mothers, compared to their respective controls. Having a RBC folate in the lowest quartile of the control distribution was associated with an O.R. of 2.56 (95% CI 1.28–5.13) for being a case and of 3.05 (95% CI 1.54–6.03) for being a case mother. The combination of homozygous mutant MTHFR genotype and RBC folate in the lowest quartile conferred an O.R. for being a NTD case of 13.43 (CI 2.49–72.33) and an O.R. for having a child with NTD of 3.28 (CI 0.84–12.85). We propose that the genetic-nutrient interaction—MTHFR polymorphism and low folate status—is associated with a greater risk for NTDs than either variable alone. Am. J. Med. Genet. 84:151–157, 1999. © 1999 Wiley-Liss, Inc.