Variation In Folate Metabolism Research Articles

Genetic variation in folate metabolism is associated with the risk of conotruncal heart defects in a Chinese population

BackgroundConotruncal heart defects (CTDs) are a subgroup of congenital heart defects that are considered to be the most common type of birth defect worldwide. Genetic disturbances in folate metabolism may increase the risk of CTDs.MethodsWe evaluated five single-nucleotide polymorphisms (SNPs) in genes related to folic acid metabolism: methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), solute carrier family 19, member 1 (SLC19A1 G80A), methionine synthase (MTR A2576G), and methionine synthase reductase (MTRR A66G), as risk factors for CTDs including various types of malformation, in a total of 193 mothers with CTD-affected offspring and 234 healthy controls in a Chinese population.ResultsLogistic regression analyses revealed that subjects carrying the TT genotype of MTHFR C677T, the C allele of MTHFR A1298C, and the AA genotype of SLC19A1 G80A had significant 2.47-fold (TT vs. CC, OR [95% CI] = 2.47 [1.42–4.32], p = 0.009), 2.05–2.20-fold (AC vs. AA, 2.05 [1.28–3.21], p = 0.0023; CC vs AA, 2.20 [1.38–3.58], p = 0.0011), and 1.68-fold (AA vs. GG, 1.68 [1.02–2.70], p = 0.0371) increased risk of CTDs, respectively. Subjects carrying both variant genotypes of MTHFR A1298C and SLC19A1 G80A had a higher (3.23 [1.71–6.02], p = 0.0002) increased risk for CTDs. Moreover, the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms were found to be significantly associated with the risk of certain subtypes of CTD.ConclusionsOur data suggest that maternal folate-related SNPs might be associated with the risk of CTDs in offspring.

Risk of congenital heart defects is influenced by genetic variation in folate metabolism

Genetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C.T, MTHFR c.1298A.C, methionine synthase reductase (MTRR) c.66A.G, and reduced folate carrier (SLC19A1) c.80A.G) in a case-control study of children (156 patients, 69 controls) and mothers of children with heart defects (181 patients, 65 controls), born before folic acid fortification. MTRR c.66A.G in children modified odds ratios for overall heart defects, specifically ventricular septal defect and aortic valve stenosis (p-value below 0.05). The 66GG and AG genotypes were associated with decreased odds ratios for heart defects (0.42, 95% confidence interval (0.18-0.97) and 0.39 (0.18-0.84), respectively). This overall association was driven by decreased risk for ventricular septal defect for 66GG and AG (odds ratio 0.32 (0.11-0.91) and 0.25 (0.09-0.65)) and decreased odds ratio for aortic valve stenosis for 66AG (0.27 (0.09-0.79)). The association of ventricular septal defect and 66AG remained significant after correction for multiple testing (p = 0.0044, multiple testing threshold p = 0.0125). Maternal MTHFR 1298AC genotype was associated with increased odds ratio for aortic valve stenosis (2.90 (1.22-6.86), p = 0.0157), but this association did not meet the higher multiple testing threshold. No association between MTHFR c.677C.T or SLC19A1 c.80A.G and heart defect risk was found. The influence of folate-related polymorphisms may be specific to certain types of heart defects; larger cohorts of mothers and children with distinct sub-classes are required to adequately address risk.

Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults

The present study examined the associations between genetic variation in folate metabolism on the one hand and cognitive functioning and mood on the other in healthy individuals. Two independent population-based samples were used, including 777 participants, aged 24-82 years, from the Maastricht Aging Study (MAAS); and 818 participants, aged 50-70 years, from the Folic Acid and Carotid Intima-Media Thickness (FACIT) study. Thymidylate synthase (TS) 2R→3R and serine hydroxymethyltransferase (SHMT1) 1420C→T polymorphisms were determined in both populations. In addition, the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T polymorphism was determined in the MAAS population. Cognitive performance was assessed in both populations using a neuropsychological test battery. In the MAAS population only, cognitive performance was retested after 12years of follow-up (n=612), and mood was measured at baseline (n=772) and 12-year follow-up (n=565) by means of the depression subscale of the Symptom Checklist 90. We found that in both study populations, cognitive performance was not associated with TS 2R→3R or SHMT1 1420C→T polymorphisms at baseline, after correction for age, sex, and level of education. The MTHFR 677C→T polymorphism was not associated with cognitive performance in the MAAS population. None of the polymorphisms in the MAAS population were related to mood at baseline or over 12 years. In conclusion, our findings do not support the involvement of genetic variation in folate metabolism in cognitive performance or mood in healthy individuals.

MTHFR polymorphisms and cognitive ageing in the ninth decade: the Lothian Birth Cohort 1921

Low blood levels of B vitamins have been implicated in age-associated cognitive impairment. The present study investigated the association between genetic variation in folate metabolism and age-related cognitive decline in the ninth decade of life. Both the 677C>T (rs1801133) polymorphism and the scarcely studied 1298A>C (rs1801131) polymorphism of the MTHFR gene were assessed in relation to cognitive change over 8 years in older community-dwelling individuals. MTHFR genotype was determined in 476 participants of the Lothian Birth Cohort 1921, whose intelligence was measured in childhood in the Scottish Mental Survey of 1932. Cognitive performance on the domains of verbal memory, reasoning and verbal fluency was assessed at mean age of 79 (n = 476) and again at mean ages of 83 (n = 275) and 87 (n = 180). Using linear mixed models, the MTHFR 677C>T and 1298A>C variants were not associated with the rate of cognitive change between 79 and 87 years, neither in the total sample, nor in a subsample of individuals with erythrocyte folate levels below the median. APOE E4 allele carrier status did not interact with MTHFR genotype in affecting change in cognitive performance over 8 years. No significant combined effect of the two polymorphisms was found. In conclusion, MTHFR 677C>T and 1298A>C polymorphisms were not associated with individual change in cognitive functioning in the ninth decade of life. Although polymorphisms in the MTHFR gene may cause disturbances in folate metabolism, they do not appear to be accompanied by changes in cognitive functioning in old age.

Acute lymphoblastic leukaemia in children – is there a role for MTHFR?

Over the last 10 years genetic variation in folate metabolism has received considerable scientific attention, but findings have been inconsistent, with many studies based on small numbers. Koppen et al (2010) recently reported on a meta-analysis of 14 studies that had investigated genetic polymorphisms in enzymes involved in folate metabolism in relation to both childhood and adult acute lymphoblastic leukaemia (ALL), concluding that both MTHFR 677 C>T and MTHFR 1298A>C were likely to be associated with decreased susceptibility to ALL in childhood. We were however, somewhat surprised to see the authors combined data from children and adults in the same plot, despite the fact that two previous meta-analyses, neither of which were referenced by Koppen et al (2010), stratified their data by diagnostic age (Pereira et al, 2006; Zintzaras et al, 2006). Indeed, the meta-analysis plots of childhood ALL (Figures 1 and ​and22 reproduced from Koppen et al, 2010) included two studies that contained no data on children at all (Skibola et al, 1999; Gemmati et al, 2004) as well as one study that comprised both children and adults (Chiusolo et al, 2004). Whilst this was acknowledged in the text in the case of the study by Gemmati et al (2004), no such recognition was afforded our ownUKstudy (Skibola et al, 1999). Moreover several published studies where no association with MTHFR 677 was observed are missing from the review, including data from Canada (Krajinovic et al, 2004)(n = 270), Turkey (Balta et al, 2003) (n = 144) and Slovenia (Petra et al, 2007) (n = 68). Fig. 1 MTHFR 677CT and susceptibility to childhood ALL reproduced from Koppen et al, 2010. Fig. 2 MTHFR 1298AC and susceptibility to childhood ALL, reproduced from Koppen et al, 2010. From their comprehensive meta analysis of 4894 individuals Pereira et al (2006) concluded that whilst the MTHFR 677 polymorphism is important for risk of ALL, it is confined to adults. This is supported by recent data from the largest study to date, which included 939 children with ALL recruited into the United Kingdom Childhood Cancer Study (http://www.UKCCS.org) (Lightfoot et al, 2010). Given the missing childhood data and the inclusion of adult data, we believe that the conclusion for a protective role for MTHFR among children drawn by the authors of the recent meta-analysis (Koppen et al, 2010), is misleading.

Genetic variation in the folate metabolic pathway and risk of childhood leukemia

AbstractStudies of childhood leukemia and the potential etiologic role of genetic variation in folate metabolism have produced conflicting findings and have often been based on small numbers. We investigated the association between polymorphisms in key folate metabolism enzymes (MTHFR 677 C>T, MTHFR 1298 A>C, SHMT1 1420 C>T, MTR 2756 A>G, TS 1494del6, and TS 28bp repeat) in 939 cases of childhood acute lymphoblastic leukemia (ALL) and 89 cases of acute myeloid leukemia (AML) recruited into the United Kingdom Childhood Cancer Study. We also examined the maternal genotypes of 752 of these cases. Data from 824 noncancer controls recruited were used for comparison. No evidence of an association with MTHFR 677 was observed for ALL or AML, either in children or their mothers. However, in children an increased risk of ALL (odds ratio [OR] = 1.88; 95% confidence interval [CI], 1.16-3.07; P = .010) and AML (OR = 2.74; 95% CI, 1.07-7.01; P = .036) was observed with the MTR 2756 GG genotype; the association was most pronounced for cases with the MLL translocation (OR = 4.90; 95% CI, 1.30-18.45; P = .019). These data suggest that genetic variation in methionine synthase could mediate risk of childhood leukemia, either via effects on DNA methylation or via effects on fetal growth and development.

Genetic selection? A study of individual variation in the enzymes of folate metabolism

BackgroundGenetic variation in folate metabolism has been associated with survival in utero, the success of in vitro fertilisation, multiple pathologies and longevity.MethodsWe have looked at the prevalence of genetic variants of the enzymes MTHFR and TYMS in 2,898 DNA samples derived from five cohorts collected in the United Kingdom. The simultaneous analysis of genetic variants of the MTHFR and TYMS loci was carried out to investigate a putative gene-gene interaction that was first observed in an elderly male population from Norfolk.ResultsWe have made a consistent observation in five population cohorts; the proportion of individuals who are homozygous for the 2R allele of the 5'UTR TYMS polymorphism is less in individuals who are homozygous for the T allele of MTHFR 677 than in individuals homozygous for the C allele of MTHFR 677 (p = 0.02).ConclusionsThese data may suggest a gene-gene interaction and could be evidence of genetic selection, with some pregnancies more or less viable as a consequence of genetic variation. If these genetic phenomena affect the way folate is handled at the cellular level in utero it is possible that maternal folic acid intake may over-ride such genetic selection.

Mathematical Modeling of Folate Metabolism: Predicted Effects of Genetic Polymorphisms on Mechanisms and Biomarkers Relevant to Carcinogenesis

Low-folate status and genetic polymorphisms in folate metabolism have been linked to several cancers. Possible biological mechanisms for this association include effects on purine and thymidine synthesis, DNA methylation, or homocysteine concentrations. The influence of genetic variation in folate metabolism on these putative mechanisms or biomarkers of cancer risk has been largely unexplored. We used a mathematical model that simulates folate metabolism biochemistry to predict (a) the effects of polymorphisms with defined effects on enzyme function (MTHFR and TS) and (b) the effects of potential, as-of-yet-unidentified polymorphisms in a comprehensive set of folate-metabolizing enzymes on biomarkers and mechanisms related to cancer risk. The model suggests that there is substantial robustness in the pathway. Our predictions were consistent with measured effects of known polymorphisms in MTHFR and TS on biomarkers. Polymorphisms that alter enzyme function of FTD, FTS, and MTCH are expected to affect purine synthesis, FTS more so under a low-folate status. In addition, MTCH polymorphisms are predicted to influence thymidine synthesis. Polymorphisms in methyltransferases should affect both methylation rates and thymidylate synthesis. Combinations of polymorphisms in MTHFR, TS, and SHMT are expected to affect nucleotide synthesis in a nonlinear fashion. These investigations provide information on effects of genetic polymorphisms on biomarkers, including those that cannot be measured well, and highlight robustness and sensitivity in this complex biological system with regard to genetic variability. Although the proportional changes in biomarkers of risk with individual polymorphisms are frequently small, they may be quite relevant if present over an individual's lifetime.

Polymorphisms involved in the folate metabolizing pathway and risk of multiple myeloma

Folate and methionine metabolism plays an essential role in both DNA synthesis and methylation. Polymorphisms in the genes of the folate-dependent enzymes have been shown to affect disease susceptibility. We conducted a Korean population-based case-control study to evaluate whether genetic variation in folate metabolism may have a role in the risk of multiple myeloma (MM). The study subjects were 173 patients with MM and 1,700 population-based controls. The polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C > T and 1298 A > C, methionine synthase (MS) 2756 A > G, methionine synthase reductase (MTRR) 66A > G, thymidylate synthase (TS) 28-bp repeat (2R-->3R) and 6-bp deletion/insertion. MS 2756 AG genotypes were associated with a 1.5-fold lower risk of MM (OR = 0.66, 95%CI; 0.43-0.99, P = 0.047). There was no association between MTHFR C677T, A1298C, MTRR A66G, TS 2R-->3R and 6-bp deletion/insertion polymorphisms and MM. These results suggest that MTHFR C677T, A1298C, MTRR A66G, TS 2R-->3R, and 6-bp deletion/insertion do not significantly factor into the pathogenesis of MM in the Korean population, but that MS A2756G polymorphism may play an important role.

Genetic Variation in the MTHFR Gene Influences Thiopurine Methyltransferase Activity

The immunosuppressive drug 6-mercaptopurine (6-MP) and its prodrug azathioprine are used in the treatment of inflammatory bowel disease and other disorders of immune regulation (1). Thiopurine methyltransferase (TPMT) inactivates 6-MP by methylation. The genetic variants TPMT *2 to *19 are associated with decreased TPMT activity (2), and TPMT*3A , * 3C , and *2 are the most common deficiency-associated variants (1). A heterozygous TPMT genotype (1 in 10 individuals from the general population) is associated with an increased risk of myelosuppression with standard-dose azathioprine therapy (3) and a favorable response to reduced-dose thiopurine therapy (1). Patients with complete TPMT deficiency (1 in 300 individuals from the general population) are at high risk for myelosuppression (4). The erythrocyte TPMT activity distribution is continuous, and concordance between genotype and phenotype in the carrier range varies, depending on where the cutoff is established between the ranges for carriers and noncarriers. We propose that genetic variation in folate metabolism influences TPMT activity and contributes to the lack of concordance between genotype and phenotype in the carrier range. TPMT irreversibly transfers a methyl group from S -adenosylmethionine (SAM) to 6-MP, forming 6-methylmercaptopurine (6-MeMP) and S -adenosylhomocysteine (SAH). The adenosyl moiety of SAH is subsequently cleaved, and homocysteine is remethylated to methionine. The methyl donor for this folate-dependent remethylation cycle is 5-methyltetrahydrofolate, which is formed from 5,10-methylenetetrahydrofolate (MTHF) in a reaction catalyzed by 5,10-MTHF reductase (MTHFR). The MTHFR 677C>T (A222V) thermolabile variant (5) and the 1298A>C (E429A) variant (6) are associated with decreased MTHFR activity. The homozygous MTHFR 677TT genotype occurs in 8%–10% of the population (7), shows 30%–50% of wild-type activity in lymphocytes (8)(9), and is associated with hyperhomocysteinemia (10), DNA hypomethylation (11), increased risk of neural tube defects(12), and decreased risk of some cancers (13)(14). The homozygous 1298CC …

Risk of Non–Hodgkin Lymphoma Associated with Polymorphisms in Folate-Metabolizing Genes

Genetic instability, including chromosomal imbalance, is important in the pathogenesis of lymphoproliferative disorders such as non-Hodgkin lymphoma (NHL). DNA synthesis and methylation, which are closely linked to folate metabolism and transport, may be affected by polymorphisms in genes involved in these pathways. Folate metabolism polymorphisms have been linked to acute lymphoblastic leukemia and colorectal cancer. To evaluate whether genetic variation in folate metabolism and transport may have a role in determining the risk of developing NHL, we analyzed several polymorphisms using DNA obtained as part of a large U.K. population-based case-control study of lymphoma. Polymorphisms studied include methylenetetrahydrofolate reductase (MTHFR) 677 C >T and 1298 A >C, methionine synthase (MTR) 2756 A>G, serine hydroxymethyltransferase (SHMT1) 1420 C >T, thymidylate synthase (TYMS) 1494del6 and 28-bp repeat, and reduced folate carrier (RFC) 80 G >A. Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant. Marginal increased risks were also observed for diffuse large B cell lymphoma with the TYMS homozygous 6 bp deletion (OR, 1.61; 95% CI, 0.99-2.60) and for follicular lymphoma with RFC 80AA (OR, 1.44; 95% CI, 0.94-2.22) and TYMS 28-bp repeat 2R/3R (OR, 1.45; 95% CI, 0.96-2.2). We observed no association between NHL and haplotypes for MTHFR or TYMS. These findings are somewhat inconsistent with those of others, but may reflect differences in circulating folate levels between study populations. Thus, further investigations are warranted in larger series with dietary information to determine the roles that genetics and folic acid status play in the etiology of lymphoma.

Colon Cancer and Genetic Variation in Folate Metabolism: The Clinical Bottom Line

So far, evidence for the relation between folate intake and colorectal cancer has been insufficient to lead to specific public health interventions. In principle, data on the relation between genetic variation in folate metabolism and colorectal neoplasia could be used to corroborate the data on the relation between folate intake or status and the disease, strengthening the evidence base for primary prevention. Issues in considering the relation between a health outcome and genetic variation in metabolism of nutrients or other food components include knowledge of gene function, linkage disequilibrium, population stratification, study size and quality, and gene-environment interaction. Overall homozygosity for MTHFR variant genotypes is associated with a reduced risk of colorectal cancer, the opposite of what might have been expected a priori. This has led investigators to place greater emphasis on the functions of folate and methylenetetrahydrofolate reductase in DNA synthesis. Folate and related nutrients may be important after adenoma formation. A challenge for the future is to characterize the effects of multiple genes influencing folate metabolism. Limited data for colorectal cancer suggest that the effect of a low folate diet overrides the effect of genotype, but two studies of adenomas suggested the opposite. Another potential role of information on genetic variation in folate metabolism is in the management of colorectal cancer but most studies have been small, have included selected patient groups, and have made limited adjustment for potentially important factors.