RESUMO
Different lifestyle patterns across Europe may influence plasma concentrations of B-vitamins and one-carbon metabolites and their relation to chronic disease. Comparison of published data on one-carbon metabolites in Western European regions is difficult due to differences in sampling procedures and analytical methods between studies. The present study aimed, to compare plasma concentrations of one-carbon metabolites in Western European regions with one laboratory performing all biochemical analyses. We performed the present study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort among 5446 presumptively healthy individuals. Quantile regression was used to compare sex-specific median concentrations between Northern (Denmark and Sweden), Central (France, Germany, The Netherlands and United Kingdom) and Southern (Greece, Spain and Italy) European regions. The lowest folate concentrations were observed in Northern Europe (men, 10·4 nmol/l; women, 10·7 nmol/l) and highest concentrations in Central Europe. Cobalamin concentrations were slightly higher in Northern Europe (men, 330 pmol/l; women, 352 pmol/l) compared with Central and Southern Europe, but did not show a clear north-south gradient. Vitamin B2 concentrations were highest in Northern Europe (men, 22·2 nmol/l; women, 26·0 nmol/l) and decreased towards Southern Europe (P trend< 0·001). Vitamin B(6) concentrations were highest in Central Europe in men (77·3 nmol/l) and highest in the North among women (70·4 nmol/l), with decreasing concentrations towards Southern Europe in women (P trend< 0·001). In men, concentrations of serine, glycine and sarcosine increased from the north to south. In women, sarcosine increased from Northern to Southern Europe. These findings may provide relevant information for the study of regional differences of chronic disease incidence in association with lifestyle.
Assuntos
Ácido Fólico/sangue , Glicina/sangue , Comportamentos Relacionados com a Saúde/etnologia , Estilo de Vida/etnologia , Sarcosina/sangue , Serina/sangue , Vitamina B 12/sangue , Adulto , Idoso , Consumo de Bebidas Alcoólicas/etnologia , Doença Crônica/etnologia , Etnicidade , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Sexuais , Fumar/etnologiaRESUMO
Two polymorphic variants in the gene coding for transcobalamin II (TCN2), TCN2 776C- > G and TCN2 67A- > G, may alter serum holotranscobalamin (holoTC), which in turn may affect cellular uptake of cobalamin (Cbl) and thereby Cbl status indicators. We studied the effects of TCN2 776C- > G and TCN2 67A- > G on blood concentrations of holoTC, Cbl, methylmalonic acid (MMA), and total homocysteine (tHcy) in 2411 individuals (50-64 y) that had been selected on the basis of these TCN2 genotypes from 10601 Norwegian inhabitants. The serum holoTC concentration was lower in TCN2 67AG (55 ± 0.75 pmol/L) and 67GG (48 ± 2.14 pmol/L) than in 67AA (62 ± 0.67 pmol/L) (P < 0.001) but did not differ among TCN2 776C- > G genotypes. The polymorphisms interacted as serum holoTC determinants (P = 0.001) and the presence of TCN2 67AG and GG in strata of 776CC and CG, but not 776GG, increased the risk of having serum holoTC < 45.6 pmol/L [tertile 1 vs. tertiles 2 and 3: OR = 2.5 (95% CI 1.8-3.5) for 67AG; OR = 5.7 (95% CI 3.5-9.1) for 67GG in 776CC; OR = 2.1 (95% CI 1.6-2.9) for 67AG; and OR = 4.5 (95% CI 2.4-8.2) for 67GG in 776CG; all P < 0.001]. Plasma MMA, tHcy, and Cbl were not affected by either polymorphism. In summary, serum holoTC, but not plasma Cbl, MMA, or tHcy, varied according to TCN2 67A- > G genotypes. It remains to be determined whether this polymorphic effect on serum holoTC alters its diagnostic utility as Cbl status indicator.
Assuntos
Polimorfismo de Nucleotídeo Único , Transcobalaminas/análise , Transcobalaminas/genética , Alelos , Biomarcadores/sangue , Estudos de Coortes , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Noruega , Estado Nutricional , Isoformas de Proteínas/sangue , Isoformas de Proteínas/genética , Fatores Sexuais , Deficiência de Vitamina B 12/sangueRESUMO
An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi-Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period. As expected with this high number of statistical tests, there were many associations with P-values<0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, P=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Ácido Fólico/metabolismo , Vitamina A/metabolismo , Feminino , Humanos , Recém-Nascido , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Large cohort studies may provide sufficient power to disentangle the role of polymorphisms related to 1-carbon metabolism and chronic diseases, but they require fast, accurate, high-throughput genotyping techniques. MALDI-TOF mass spectrometry has been adapted to rapid fine mapping using various approaches for allele discrimination. We developed a genotyping method based on MALDI-TOF MS and compared assay performance for formats based on standard and mass-modified terminators. METHODS: The assay includes 20 polymorphisms of 14 genes involved in 1-carbon metabolism (BHMT 742G>A, CBS 844ins68 and 699C>T, CTH 1364G>T, DHFR del19, NOS3 -786T>C and 894G>T, FOLR1 1314G>A, MTHFD1 -105T>C and 1958G>A, MTHFR 677C>T and 1298A>C, MTR 2756A>G, MTRR 66A>G and 524C>T, SLC19A1 80G>A, SHMT1 1420C>T, TCN2 67A>G and 776C>G, and TYMS 1494del6). RESULTS: Missing calls were observed for 4.7% of the DNA samples, attributed to failed liquid sample handling. Highly accurate genotyping was obtained by mass-modified as well as standard ddNTPs, with an average error rate of < or =0.1% by analysis of sample duplicates. A semiquantitative approach enabled unambiguous identification of the CBS 844ins68. Cluster plots of the relative allele intensities showed allele-specific bias according to type of minisequencing terminator and revealed a potential structural variation in the BHMT gene. CONCLUSIONS: MALDI-TOF MS-based genotyping using either standard or mass-modified terminators allows the accurate determination of single nucleotides as well as structural genetic variants. This was demonstrated with 20 polymorphisms involved in 1-carbon metabolism.
Assuntos
Carbono/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Alelos , Betaína-Homocisteína S-Metiltransferase/genética , DNA/genética , DNA/isolamento & purificação , Variação Genética , Genótipo , Humanos , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Glycine is a precursor of purines, protein, glutathione, and 1-carbon units as 5,10-methylenetetrahydrofolate. Glycine decarboxylation through the glycine cleavage system (GCS) and glycine-serine transformation by serine hydroxymethyltransferase (SHMT) require pyridoxal 5'-phosphate (PLP; active form of vitamin B-6) as a coenzyme. The intake of vitamin B-6 is frequently low in humans. Therefore, we determined the effects of vitamin B-6 restriction on whole-body glycine flux, the rate of glycine decarboxylation, glycine-to-serine conversion, use of glycine carbons in nucleoside synthesis, and other aspects of 1-carbon metabolism. We used a primed, constant infusion of [1,2-(13)C(2)]glycine and [5,5,5-(2)H(3)]leucine to quantify in vivo kinetics in healthy adults (7 males, 6 females; 20-39 y) of normal vitamin B-6 status or marginal vitamin B-6 deficiency. Vitamin B-6 restriction lowered the plasma PLP concentration from 55 +/- 4 nmol/L (mean +/- SEM) to 23 +/- 1 nmol/L (P < 0.0001), which is consistent with marginal deficiency, whereas the plasma glycine concentration increased (P < 0.01). SHMT-mediated conversion of glycine to serine increased from 182 +/- 7 to 205 +/- 9 micromol x kg(-1) x h(-1) (P < 0.05), but serine production using a GCS-derived 1-carbon unit (93 +/- 9 vs. 91 +/- 6 micromol x kg(-1) x h(-1)) and glycine cleavage (163 +/- 11 vs. 151 +/- 8 micromol x kg(-1) x h(-1)) were not changed by vitamin B-6 restriction. The GCS produced 1-carbon units at a rate (approximately 140-170 micromol x kg(-1) x h(-1)) that greatly exceeds the demand for remethylation and transmethylation processes (approximately 4-7 micromol x kg(-1) x h(-1)). We conclude that the in vivo GCS and SHMT reactions are quite resilient to the effects of marginal vitamin B-6 deficiency, presumably through a compensatory effect of increasing substrate concentration.
Assuntos
Cistationina/sangue , Glicina/sangue , Glicina/metabolismo , Deficiência de Vitamina B 6/sangue , Vitamina B 6/farmacologia , Adulto , Dieta , Feminino , Humanos , Masculino , Serina/sangue , Serina/metabolismo , Tetra-Hidrofolatos/metabolismo , Deficiência de Vitamina B 6/metabolismo , Adulto JovemRESUMO
Folate metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with or without cleft palate (CL/P) and 191 families with cleft palate only (CPO). We previously showed a 39% reduction in risk of CL/P with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (>400 microg) to explore gene-exposure interactions. We found a reduced risk of CL/P with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% CI 0.63-1.4) and 0.50 (95% CI 0.26-0.96) with two copies (P = 0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts.
Assuntos
Carbono/metabolismo , Fenda Labial/genética , Fissura Palatina/genética , Ácido Fólico/metabolismo , Redes e Vias Metabólicas/genética , Polimorfismo Genético , Estudos de Casos e Controles , Suplementos Nutricionais , Feminino , Ácido Fólico/farmacologia , Frequência do Gene , Humanos , Recém-Nascido , Masculino , Modelos Biológicos , GravidezRESUMO
Several polymorphisms of genes involved in one-carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large-scale study of 10,601 population-based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one-carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B(12) (cobalamin), methylmalonic acid (MMA), vitamin B(2) (riboflavin), vitamin B(6) (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase (MTHFR) c.665C>T (known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala); methionine synthase (MTR) c.2756A>G (p.Asp919Gly); methionine synthase reductase (MTRR) c.66A>G (p.Ile22Met); methylenetetrahydrofolate dehydrogenase (MTHFD1) c.1958G>A (p.Arg653Gln); betaine homocysteine methyltransferase (BHMT) c.716G>A (known as 742G>A; p.Arg239Gln); cystathionine beta-synthase (CBS) c.844_845ins68 and c.699C>T (p.Tyr233Tyr); transcobalamin-II (TCN2) c.67A>G (p.Ile23Val) and c.776C>G (p.Pro259Arg); reduced folate carrier-1 (SLC19A1) c.80G>A (p.Arg27His); and paraoxonase-1 (PON1) c.163T>A (p.Leu55Met) and c.575A>G (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665C>T with tHcy and folate, but also observed significant (P<0.01) changes in metabolite concentrations according to other gene polymorphisms. These include MTHFR c.1286A>C (associations with tHcy, folate and betaine), MTR c.2756A>G (tHcy), BHMT c.716G>A (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699C>T (tHcy, betaine, cystathionine) and TCN2 c.776C>G (MMA). No associations were observed for the other polymorphisms investigated.
Assuntos
Carbono/metabolismo , Testes Genéticos , Doenças Metabólicas/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Modelos BiológicosRESUMO
Previous studies have shown inconsistent associations of folate intake and polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene with gastric cancer risk. Our nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort is the first prospective study of blood folate levels and gastric cancer. Gastric cancer cases (n=247) and controls (n=631) were matched for study center, age, sex, and time of blood donation. Two common single nucleotide polymorphisms of the MTHFR gene were determined, as were plasma concentrations of folate, cobalamin (vitamin B12), total homocysteine, and methylmalonic acid (cobalamin deficiency marker) in prediagnostic plasma. Risk measures were calculated with conditional logistic regression. Although no relations were observed between plasma folate or total homocysteine concentrations and gastric cancer, we observed a trend toward lower risk of gastric cancer with increasing cobalamin concentrations (odds ratio, 0.79 per SD increase in cobalamin; P=0.01). Further analyses showed that the inverse association between cobalamin and gastric cancer was confined to cancer cases with low pepsinogen A levels (marker of severe chronic atrophic gastritis) at the time of blood sampling. The 677 C-->T MTHFR polymorphism was not associated with gastric cancer, but we observed an increased risk with the variant genotype of the 1298 A-->C polymorphism (odds ratio, 1.47 for CC versus AA; P=0.04). In conclusion, we found no evidence of a role of folate in gastric cancer etiology. However, we observed increased gastric cancer risk at low cobalamin levels that was most likely due to compromised cobalamin status in atrophic gastritis preceding gastric cancer.
Assuntos
Ácido Fólico/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genética , Vitamina B 12/sangue , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Gastrite Atrófica/sangue , Gastrite Atrófica/epidemiologia , Homocisteína/sangue , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Ácido Metilmalônico/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologiaRESUMO
BACKGROUND: Although individual studies have been inconsistent, meta-analyses of epidemiological data suggest that high folate and vitamin B12 levels may be associated with increased prostate cancer risk. METHODS: Within JANUS, a prospective cohort in Norway (n = 317 000) with baseline serum samples, we conducted a nested case-control study among 3000 prostate cancer cases and 3000 controls, matched on age and time at serum sampling, and county of residence. Using conditional logistic regression, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer risk were estimated according to quintiles of serum folate, vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy) and methionine, and according to MTHFR 677CâT genotypes. To correct for degradation during sample storage, folate concentration was measured as p-aminobenzoylglutamate (pABG) equivalents following oxidation and acid hydrolysis. RESULTS: We observed a weak positive association between folate concentration and prostate cancer risk [OR highest vs lowest quintile = 1.15 (0.97-1.37), P-trend = 0.04], which was more pronounced among individuals ≥ 50 years at inclusion [OR 1.40 (1.07-1.84), P-trend = 0.02]. tHcy showed an inverse trend with risk [OR 0.92 (0.77-1.10), P-trend = 0.03]. Vitamin B12, MMA and methionine concentrations were not associated with prostate cancer risk. Compared with the MTHFR 677CC genotype, the CT and TT variants, both of which were related to lower folate concentrations, were associated with reduced prostate cancer risk [OR 0.82 (0.72-0.94) and OR 0.78 (0.64-0.94), respectively]. CONCLUSION: This large-scale population-based study suggests that high serum folate concentration may be associated with modestly increased prostate cancer risk. We did not observe an association between vitamin B12 status and prostate cancer risk.
Assuntos
Ácido Fólico/sangue , Neoplasias da Próstata/sangue , Vitamina B 12/sangue , Adulto , Idoso , Estudos de Casos e Controles , Intervalos de Confiança , Genótipo , Homocisteína/sangue , Humanos , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Noruega , Razão de Chances , Reação em Cadeia da Polimerase , Polimorfismo Genético , Vigilância da População , Estudos Prospectivos , Neoplasias da Próstata/genética , Fatores de Risco , Fatores SocioeconômicosRESUMO
BACKGROUND: Efficient one-carbon metabolism, which requires adequate supply of methyl group donors and B-vitamins, may protect against colorectal carcinogenesis. However, plasma folate and vitamins B2 and B12 have inconsistently been associated with colorectal cancer risk, and there have been no previous studies relating plasma concentrations of methionine, choline, and betaine to this outcome. METHODS: This study comprised 10,601 individuals, 50 to 64 years of age, participating in the Norwegian Colorectal Cancer Prevention (NORCCAP) screening study. Using logistic regression analyses, we crosssectionally investigated associations between distal colorectal adenoma occurrence-potential precursor lesions of colorectal carcinomas-and plasma concentrations of methyl group donors and B-vitamins, and polymorphisms of genes related to one-carbon metabolism. RESULTS: Screening revealed 1,809 subjects (17.1%) with at least one adenoma. The occurrence of high-risk adenomas (observed in 421 subjects) was inversely associated with plasma concentrations of methionine (highest versus lowest quartile: odds ratio (OR) = 0.61; 95% confidence interval (CI) = 0.45-0.83), betaine: OR = 0.74; 95% CI = 0.54-1.02, the vitamin B2 form flavin-mononucleotide (FMN): OR = 0.65; 95% CI = 0.49-0.88, and the vitamin B6 form pyridoxal 5'-phosphate (PLP): OR = 0.69; 95% CI = 0.51-0.95, but not with folate, choline, vitamin B12 concentrations, or with the studied polymorphisms. High methionine concentration in combination with high vitamin B2 or B6 concentrations was associated with lower occurrence of high-risk adenomas compared with these factors individually. CONCLUSIONS: High plasma concentrations of methionine and betaine, and vitamins B2 and B6 may reduce risk of developing colorectal adenomas. IMPACT: In addition to B-vitamins, methyl group donors such as methionine and betaine may play a role in colorectal carcinogenesis.
Assuntos
Adenoma/sangue , Betaína/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Metionina/sangue , Riboflavina/sangue , Vitamina B 6/sangue , Adenoma/epidemiologia , Adenoma/genética , Adenoma/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Polimorfismo Genético , Fatores de RiscoRESUMO
BACKGROUND: B-vitamins are essential for one-carbon metabolism and have been linked to colorectal cancer. Although associations with folate have frequently been studied, studies on other plasma vitamins B2, B6, and B12 and colorectal cancer are scarce or inconclusive. METHODS: We carried out a nested case-control study within the European Prospective Investigation into Cancer and Nutrition, including 1,365 incident colorectal cancer cases and 2,319 controls matched for study center, age, and sex. We measured the sum of B2 species riboflavin and flavin mononucleotide, and the sum of B6 species pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid as indicators for vitamin B2 and B6 status, as well as vitamin B12 in plasma samples collected at baseline. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for colorectal cancer were estimated using conditional logistic regression, adjusted for smoking, education, physical activity, body mass index, alcohol consumption, and intakes of fiber and red and processed meat. RESULTS: The relative risks comparing highest to lowest quintile were 0.71 [95% confidence interval (95% CI), 0.56-0.91; P(trend) = 0.02] for vitamin B2, 0.68 (95% CI, 0.53-0.87; P(trend) <0.001) for vitamin B6, and 1.02 (95% CI, 0.80-1.29; P(trend) = 0.19) for vitamin B12. The associations for vitamin B6 were stronger in males who consumed ≥30 g alcohol/day. The polymorphisms were not associated with colorectal cancer. CONCLUSIONS: Higher plasma concentrations of vitamins B2 and B6 are associated with a lower colorectal cancer risk. IMPACT: This European population-based study is the first to indicate that vitamin B2 is inversely associated with colorectal cancer, and is in agreement with previously suggested inverse associations of vitamin B6 with colorectal cancer.
Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Ácido Fólico/sangue , Riboflavina/sangue , Vitamina B 12/sangue , Vitamina B 6/sangue , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/prevenção & controle , Feminino , Ácido Fólico/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Riboflavina/genética , Fatores de Risco , Vitamina B 12/genética , Vitamina B 6/genéticaRESUMO
B vitamins and polymorphisms in genes coding for enzymes involved in one-carbon metabolism may affect DNA synthesis and methylation and thereby be implicated in carcinogenesis. Previous data on vitamins B2 and B6 and genetic polymorphisms other than those involving MTHFR as risk factors for gastric cancer (GC) are sparse and inconsistent. In this case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort, cases (n = 235) and controls (n = 601) were matched for study center, age, sex, and time of blood sampling. B2 and B6 species were measured in plasma, and the sum of riboflavin and flavin mononucleotide was used as the main exposure variable for vitamin B2 status, whereas the sum of pyridoxal 5'-phosphate, pyridoxal, and 4-pyridoxic acid was used to define vitamin B6 status. In addition, we determined eight polymorphisms related to one-carbon metabolism. Relative risks for GC risk were calculated with conditional logistic regression, adjusted for Helicobacter pylori infection status and smoking status. Adjusted relative risks per quartile (95% confidence interval, P(trend)) were 0.85 (0.72-1.01, 0.06) for vitamin B2 and 0.78 (0.65-0.93, <0.01) for vitamin B6. Both relations were stronger in individuals with severe chronic atrophic gastritis. The polymorphisms were not associated with GC risk and did not modify the observed vitamin-cancer associations. In summary, results from this large European cohort study showed an inverse association between vitamin B2 and GC risk, which is borderline significant, and a significant inverse association between vitamin B6 and GC risk.
Assuntos
Adenocarcinoma/genética , Transferases de Grupo de Um Carbono/genética , Riboflavina/sangue , Neoplasias Gástricas/genética , Vitamina B 6/sangue , Adenocarcinoma/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias Gástricas/metabolismoRESUMO
BACKGROUND: A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. We investigate the associations between plasma folate, several relevant folate-related polymorphisms, and CRC risk within the large European Prospective Investigation into Cancer and Nutrition cohort. METHODS: In this nested case-control study, 1,367 incident CRC cases were matched to 2,325 controls for study center, age, and sex. Risk ratios (RR) were estimated with conditional logistic regression and adjusted for smoking, education, physical activity, and intake of alcohol and fiber. RESULTS: Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% confidence interval; Ptrend) for the fifth versus the first quintile of folate status was 0.94 (0.74-1.20; 0.44). The polymorphisms MTHFR677C-->T, MTHFR1298A-->C, MTR2756A-->G, MTRR66A-->G, and MTHFD11958G-->A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically nonsignificant increased CRC risk [RR (95% CI; Ptrend) TT versus CC=1.39 (0.87-2.21); 0.12], whereas those with the highest folate concentrations showed a nonsignificant decreased CRC risk [RR TT versus CC=0.74 (0.39-1.37); 0.34]. The SLC19A180G-->A showed a positive association with CRC risk [RR AA versus GG 1.30 (1.06-1.59); <0.01]. CONCLUSIONS: This large European prospective multicenter study did not show an association of CRC risk with plasma folate status nor with MTHFR polymorphisms. IMPACT: Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions.
Assuntos
Neoplasias Colorretais/genética , Ácido Fólico/sangue , Ácido Fólico/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
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 < or = 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.
Assuntos
Estudos Epidemiológicos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Nucleotídeos de Adenina/genética , Nucleotídeos de Citosina/genética , Feminino , Ácido Fólico/sangue , Ácido Fólico/genética , Genótipo , Homocisteína/sangue , Homocisteína/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/fisiologia , Pessoa de Meia-Idade , Nucleotídeos de Timina/genéticaRESUMO
BACKGROUND: Increased plasma total homocysteine (tHcy), a risk factor for cardiovascular disease, is related to genetic, environmental, and nutritional factors, in particular folate status. Future large epidemiologic studies of the genetic basis of hyperhomocysteinemia will require high-throughput assays for polymorphisms of genes related to folate and Hcy metabolism. METHOD: We developed a high-level multiplex genotyping method based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for the detection of 12 polymorphisms in 8 genes involved in folate or Hcy metabolism. The assay includes methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, cystathionine beta-synthase (CBS) 844ins68 and 699C>T, transcobalamin II (TCII) 776C>G and 67A>G, reduced folate carrier-1 (RFC1) 80G>A, paraoxonase-1 (PON1) 575A>G and 163T>A, and betaine homocysteine methyltransferase (BHMT) 742G>A. RESULTS: The failure rate of the assay was < or = 1.7% and was attributable to unsuccessful DNA purification, nanoliter dispensing, and spectrum calibration. Most errors were related to identification of heterozygotes as homozygotes. The mean error rate was 0.26%, and error rates differed for the various single-nucleotide polymorphisms. Identification of CBS 844ins68 was carried out by a semiquantitative approach. The throughput of the MALDI-TOF MS assay was 1152 genotypes within 20 min. CONCLUSIONS: This high-level multiplex method is able to genotype 12 polymorphisms involved in folate or Hcy metabolism. The method is rapid and reproducible and could facilitate large-scale studies of the genetic basis of hyperhomocysteinemia and associated pathologies.
Assuntos
Ácido Fólico/metabolismo , Homocisteína/metabolismo , Polimorfismo Genético , Genótipo , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Serious complications of homocystinuria caused by cystathionine beta-synthase deficiency can be prevented by early intervention. We determined the prevalence of 6 specific mutations in 1133 newborn blood samples. Our results suggest that homocystinuria is more common than previously reported. Newborn screening for homocystinuria through mutation detection should be further considered.
Assuntos
Cistationina beta-Sintase/genética , Homocistinúria/epidemiologia , Homocistinúria/genética , Mutação , Feminino , Humanos , Recém-Nascido , Epidemiologia Molecular , Triagem Neonatal , Noruega/epidemiologia , PrevalênciaRESUMO
BACKGROUND: Newborn screening for total homocysteine (tHcy) in blood may identify babies with vitamin B12 (B12) deficiency or homocystinuria, but data on the causes of increased tHcy in screening samples are sparse. METHODS: Serum concentrations of tHcy, cystathionine, methionine, folate, and B12 and the methylenetetrahydrofolate reductase (MTHFR) 677C > T polymorphism were determined in 4992 capillary blood samples collected as part of the routine screening program in newborn children. Methylmalonic acid (MMA), gender (SRY genotyping), and the frequency of six cystathionine beta-synthase (CBS) mutations were determined in 20-27% of the samples, including all samples with tHcy > 15 micromol/L (n = 127), B12 < 100 pmol/L (n = 159), or methionine > 40 micromol/L (n = 154). RESULTS: The median (5th-95th percentile) tHcy concentration was 6.8 (4.2-12.8) micromol/L. B12 status, as determined by serum concentrations of B12, tHcy, and MMA, was moderately better in boys than in girls. tHcy concentrations between 10 and 20 micromol/L were often associated with low B12, whereas tHcy > 20 micromol/L (n = 43) was nearly always explained by increased methionine. tHcy did not differ according to folate concentrations or MTHFR 677C > T genotypes. None of the babies had definite CBS deficiencies, but heterozygosity led to low cystathionine, increased methionine, but normal tHcy concentrations. CONCLUSION: Increased tHcy is a common but not specific finding in newborns. The metabolite and vitamin profiles will point to the cause of hyperhomocysteinemia. Screening for tHcy and related factors should be further evaluated in regions with high prevalence of homocystinuria and in babies at high risk of B12 deficiency.