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Folate in cancer and cardiovascular disease: prospective studies from the population-based northern Sweden health and disease study
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

BACKGROUND: Folate, a B-vitamin found primarily in fruits and vegetables, especially leafy greens, and other B-vitamins involved in folate metabolism are believed to protect against cancer and cardiovascular disease. Maintaining an adequate folate status ensures availability of methyl groups for DNA synthesis and for all methylation reactions in the body, and prevents the accumulation of homocysteine, a sulphur-containing amino acid that has been linked to cardiovascular disease. The aim of this thesis was to relate factors involved in folate metabolism to the risk of developing colorectal cancer (CRC), prostate cancer (PCa), stroke (ischemic and hemorrhagic), and acute myocardial infarction (AMI).

SUBJECTS AND METHODS: These were nested case-referent studies, with 226 CRC, 254 PCa, 396 stroke (334 ischemic and 62 hemorrhagic), and 571 AMI cases, and double, matched referents from the population-based Northern Sweden Health and Disease Study.

CRC RESULTS: A bell-shaped association was observed between plasma folate concentrations and the risk of CRC [multivariate odds ratio (OR) for the middle versus lowest quintile, 2.00 (95% CI 1.13-3.56)]. Homocysteine was not associated with CRC risk. A reduced risk was observed for the MTHFR 677C>T polymorphism [OR for TT versus CC, 0.41 (95% CI 0.19-0.85), Ptrend=0.062] that was independent of plasma folate status. Prediagnostic plasma folate concentrations were higher in cases with promoter hypermethylation in the p16 and/or hMLH1 tumor suppressor genes in CRC tissue compared to cases without promoter hypermethylation in these genes (P=0.025).

PCa RESULTS: Increasing plasma levels of folate and vitamin B12 were associated with increased risk of PCa [OR for the highest versus lowest quartile, 1.60 (95% CI 1.03-2.49), Ptrend=0.02 for folate, and 2.63 (95% CI 1.61-4.29), Ptrend<0.001 for vitamin B12]. Increasing plasma homocysteine levels were associated with a reduced risk of borderline significance. In multivariate analyses, the risk estimate remained statistically significant only for vitamin B12.

STROKE RESULTS: Plasma folate concentrations were associated with the risk of hemorrhagic stroke in an inverse linear manner after adjustment for conventional risk factors including hypertension [multivariate OR for the highest versus lowest quartile, 0.21 (95% CI 0.06-0.71), Ptrend=0.008]. Risk estimates were attenuated by the inclusion of homocysteine in the model [OR 0.34 (95% CI 0.08-1.40), Ptrend=0.088]. Similar results were obtained for folate intake. Neither plasma folate levels nor folate intake demonstrated a clear association with the risk of ischemic stroke, and neither plasma nor dietary vitamin B12 was associated with the risk of either type of stroke.

AMI RESULTS: Plasma folate concentrations demonstrated an inverse association with risk of AMI that was independent of other risk factors, including homocysteine [multivariate OR for the highest versus lowest quintile, 0.56 (95% CI 0.34-0.90), Ptrend=0.080]. For vitamin B12, no clear risk relationships were apparent. None of the risk estimates for dietary intake of folate, vitamin B12, vitamin B6, or vitamin B2 were statistically significant, although the results for folate and vitamin B12 intake were in line with those for the plasma variables.

CONCLUSIONS: The results of these population-based, prospective studies suggest that although a high folate status may be associated with a reduced risk of cardiovascular diseases, the relationship with cancer risk seems to be more complicated. The possibility of a detrimental component to the role of folate and vitamin B12 in carcinogenesis may have implications in the ongoing debate concerning mandatory folate fortification of foods.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2006. , 91 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1049
National Category
Clinical Laboratory Medicine
Research subject
Medical Biochemistry
Identifiers
URN: urn:nbn:se:umu:diva-850ISBN: 91-7264-159-2 (print)OAI: oai:DiVA.org:umu-850DiVA: diva2:144729
Public defence
2006-09-22, Hörsal Betula, 6M, Umeå, 13:00 (English)
Opponent
Available from: 2006-09-04 Created: 2006-09-04 Last updated: 2012-02-03Bibliographically approved
List of papers
1. Low folate levels may protect against colorectal cancer
Open this publication in new window or tab >>Low folate levels may protect against colorectal cancer
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2006 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 55, no 10, 1461-1466 p.Article in journal (Other academic) Published
Abstract [en]

BACKGROUND AND AIMS: Dietary folate is believed to protect against colorectal cancer (CRC). However, few studies have addressed the role of circulating levels of folate. The aim of this study was to relate prediagnostic plasma folate and homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms to the risk of developing CRC.

SUBJECTS: Subjects were 226 cases and 437 matched referents from the population based Northern Sweden Health and Disease Cohort.

RESULTS: We observed a bell-shaped association between plasma folate concentrations and CRC risk; multivariate odds ratio for middle versus lowest quintile 2.00 (95% confidence interval (CI) 1.13-3.56). In subjects with follow up times greater than the median of 4.2 years however, plasma folate concentrations were strongly positively related to CRC risk; multivariate odds ratio for highest versus lowest quintile 3.87 (95% CI 1.52-9.87; p trend = 0.007). Homocysteine was not associated with CRC risk. Multivariate odds ratios for the MTHFR polymorphisms were, for 677 TT versus CC, 0.41 (95% CI 0.19-0.85; p trend = 0.062), and for 1298 CC versus AA, 1.62 (95% CI 0.94-2.81; p trend = 0.028). Interaction analysis suggested that the result for 1298A>C may have been largely due to linkage disequilibrium with 677C>T. The reduced CRC risk in 677 TT homozygotes was independent of plasma folate status.

CONCLUSIONS: Our findings suggest a decreased CRC risk in subjects with low folate status. This possibility of a detrimental component to the role of folate in carcinogenesis could have implications in the ongoing debate in Europe concerning mandatory folate fortification of foods.

National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-15280 (URN)10.1136/gut.2005.085480 (DOI)16638790 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically approved
2. Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study.
Open this publication in new window or tab >>Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study.
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2005 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 113, no 5, 819-824 p.Article in journal (Refereed) Published
Abstract [en]

The role of folate metabolism in cancer development is a topic of much current interest, with maintenance of adequate folate status tending to show a protective effect. Aberrant methylation, primarily hypermethylation of certain genes including tumor suppressors, has been implicated in prostate cancer development. Folate, vitamin B12 and homocysteine are essential for methyl group metabolism and thus also for DNA methylation. We related plasma levels of these factors to prostate cancer risk in a prospective study of 254 case subjects and 514 matched control subjects. Increasing plasma levels of folate and vitamin B12 were statistically significantly associated with increased prostate cancer risk, with an odds ratio of 1.60 (95% CI = 1.03-2.49; p(trend) = 0.02) for folate and 2.63 (95% CI = 1.61-4.29; p(trend) < 0.001) for vitamin B12 for highest vs. lowest quartile. Increasing plasma homocysteine levels were associated with a reduced risk of borderline significance (OR = 0.67; 95% CI = 0.43-1.04; p(trend) = 0.08). After adjustment for the other 2 plasma variables, body mass index and smoking, a statistically significant increased risk remained only for vitamin B12 (OR = 2.96; 95% CI = 1.58-5.55; p(trend) = 0.001). Adjusted OR for folate and homocysteine were 1.30 (95% CI = 0.74-2.24; p(trend) = 0.17) and 0.91 (95% CI = 0.51-1.58; p(trend) = 0.60), respectively. Our results suggest that factors contributing to folate status are not protective against prostate cancer. On the contrary, vitamin B12, associated with an up to 3-fold increase in risk, and possibly also folate, may even stimulate prostate cancer development. These findings are novel and should be explored further in future studies. (c) 2004 Wiley-Liss, Inc.

Keyword
Adult, Aged, Bone Neoplasms/blood/etiology/secondary, Case-Control Studies, Folic Acid/*blood, Homocysteine/*blood, Humans, Lymphatic Metastasis, Male, Middle Aged, Prospective Studies, Prostatic Neoplasms/blood/*epidemiology/*etiology, Risk Factors, Sweden/epidemiology, Vitamin B 12/*blood
Identifiers
urn:nbn:se:umu:diva-14262 (URN)10.1002/ijc.20646 (DOI)15499634 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically approved
3. Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: a prospective, nested case-referent study of plasma concentrations and dietary intake.
Open this publication in new window or tab >>Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: a prospective, nested case-referent study of plasma concentrations and dietary intake.
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2005 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 36, no 7, 1426-1431 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Folate metabolism has been implicated in stroke. However, the possibility of a role for folate and vitamin B12, independent of their effects on homocysteine status, remains to be explored. The aim of this prospective, nested case-referent study was to relate plasma and dietary intake levels of folate and vitamin B12 to risk of stroke, taking into consideration plasma homocysteine concentrations and methylenetetrahydrofolate reductase polymorphisms. METHODS: Subjects were 334 ischemic and 62 hemorrhagic stroke cases and matched double referents from the population-based Northern Sweden Health and Disease Cohort. RESULTS: Plasma folate was statistically significantly associated with risk of hemorrhagic stroke in an inverse linear manner, both in univariate analysis and after adjustment for conventional risk factors including hypertension (odds ratio [OR] for highest versus lowest quartile 0.21 (95% confidence interval [CI], 0.06 to 0.71; P for trend=0.008)). Risk estimates were attenuated by inclusion of homocysteine in the model (OR, 0.34; 95% CI, 0.08 to 1.40; P for trend=0.088). A similar pattern was observed for increasing folate intake (multivariate OR, 0.07; 95% CI, 0.01 to 0.55; P for trend=0.031 without homocysteine, and OR, 0.16, 95% CI, 0.02 to 1.23; P for trend=0.118 with homocysteine in the analysis). We found little evidence of an association between plasma or dietary folate and risk of ischemic stroke. Neither plasma nor dietary vitamin B12 was associated with risk of either stroke subtype. CONCLUSIONS: The results of this study suggest a protective role for folate, possibly in addition to its effects on homocysteine status, in hemorrhagic but not ischemic stroke.

Keyword
Adult, Aged, Brain Ischemia/etiology/*pathology, Case-Control Studies, Cerebrovascular Accident/etiology/*pathology, Cohort Studies, Diet, Female, Folic Acid/blood/*pharmacology, Hemorrhage/blood, Homocysteine/blood, Humans, Male, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, Middle Aged, Multivariate Analysis, Nutritional Status, Odds Ratio, Polymorphism; Genetic, Prospective Studies, Registries, Risk, Sweden, Vitamin B 12/*pharmacology
Identifiers
urn:nbn:se:umu:diva-15037 (URN)doi:10.1161/01.STR.0000169934.96354.3a (DOI)15933256 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2017-12-14Bibliographically approved
4. Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function
Open this publication in new window or tab >>Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function
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2009 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 266, no 2, 182-195 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To investigate the relationship between plasma folate, vitamin B12 and total homocysteine concentrations, dietary intake of folate and vitamins B12, B6 and B2, and the risk of first acute myocardial infarction (MI). DESIGN: Nested case-referent study with up to 13 years of follow-up. SETTING: The population-based Northern Sweden Health and Disease Study, with 73 879 participants at the time of case ascertainment. SUBJECTS: A total of 571 MI cases (406 men) and 1569 matched referents. Of the cases, 530 had plasma samples available, and 247 had dietary B-vitamin intake data. RESULTS: Plasma concentrations of folate were inversely associated, and total homocysteine positively associated, with the risk of MI, independently of each other and of a number of established and novel cardiovascular risk factors, including renal function [multivariate odds ratio for highest vs. lowest quintile of folate 0.52 (95% CI 0.31-0.84), P for trend = 0.036, and homocysteine 1.92 (95% CI 1.20-3.09), P for trend = 0.006]. For plasma vitamin B12 concentrations, and vitamin B12, B6 and B2 intake, no clear risk relationship was apparent. Though not statistically significant, the results for folate intake were consistent with those for plasma concentrations. CONCLUSIONS: In this large prospective study of a population without mandatory folic acid fortification, both folate and homocysteine were strongly associated with the risk of myocardial infarction, independently of each other and of renal function. Although randomized trials of folic acid supplementation are needed to determine causality, our findings highlight the potential importance of folate, or sources of folate, in incident cardiovascular disease.

Keyword
acute myocardial infarction, cardiovascular risk factors, cobalamin, folic acid, homocysteine, renal function
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-25589 (URN)10.1111/j.1365-2796.2009.02077.x (DOI)000267883100003 ()19298497 (PubMedID)
Available from: 2009-08-21 Created: 2009-08-21 Last updated: 2017-12-13Bibliographically approved

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