Folate and homocysteine interrelationships including genetics of the relevant enzymes

Current Opinion in Lipidology

Volumn 15, Issue 1, 2004, Pages 49-57

  Molloy, Anne M ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

5,10 methylenetetrahydrofolate reductase; Cardiovascular disease; Folate; Genetic variance; Homocysteine; Vitamin B12

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); FOLIC ACID; HOMOCYSTEINE; RIBOFLAVIN;

AMINO ACID BLOOD LEVEL; BIRTH DEFECT; CANCER; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; COGNITIVE DEFECT; DISEASE PREDISPOSITION; DNA POLYMORPHISM; FOLATE METABOLISM; FOLIC ACID DEFICIENCY; GENETIC VARIABILITY; GENETICS; HUMAN; PREGNANCY COMPLICATION; PRIORITY JOURNAL; REVIEW; RISK FACTOR;

FOLIC ACID; HOMOCYSTEINE; HUMANS; METHYLENETETRAHYDROFOLATE DEHYDROGENASE (NAD+);

EID: 4344715540     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/00041433-200402000-00010     Document Type: Review

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101. McNulty H, McKinley MC, Wilson B, et al. Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. Am J Clin Nutr 2002; 76:436-441. This important study demonstrates the requirement of TT homozygotes for adequate riboflavin, irrespective of their folate status. Differences between this study and Ref. [100] probably reflect a higher underlying riboflavin status in the US due to riboflavin fortification of the diet.
102. Moat SJ, Ashfield-Watt PA, Powers HJ, et al. Effect of riboflavin status on the homocysteine-lowering effect of folate in relation to the MTHFR (C677T) genotype. Clin Chem 2003; 49:295-302. This is the first intervention study to examine the interaction between riboflavin and folate in lowering homocysteine.
103. Pepe G, Camacho Vanegas O, Giusti B, et al. Heterogeneity in world distribution of the thermolabile C677T mutation in 5,10- methylenetetrahydrofolate reductase. Am J Hum Genet 1998; 63:917-920.
104. Cappuccio FP, Bell R, Perry IJ, et al. Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis 2002; 164:95-102.
105. Esfahani ST, Cogger EA, Caudill MA. Heterogeneity in the prevalence of methylenetetrahydrofolate reductase gene polymorphisms in women of different ethnic groups. J Am Diet Assoc 2003; 103:200-207. This reasonably sized study demonstrates wide variations in the prevalence of the 677 polymorphism between ethnic groups and completely different profiles for the 1298 variant.
106. ••] give genetic support to the hypothesis that elevated homocysteine causes vascular disease.
107. Meleady R, Ueland PM, Blom H, et al. Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project. Am J Clin Nutr 2003; 77:63-70. This paper concludes the MTHFR 677C→T variant confers modest risk of vascular disease because it is a cause of elevated plasma homocysteine and low folate status. These data support the conclusion of the two metaanalyses relating MTHFR to vascular disease.
108. ••], although the emphasis was on low folate status rather than elevated homocysteine. The authors concluded that the variant conferred risk only in association with low folate.
109. Mennen LI, de Courcy GP, Guilland JC, et al. Homocysteine, cardiovascular disease risk factors, and habitual diet in the French Supplementation with Antioxidant Vitamins and Minerals Study. Am J Clin Nutr 2002; 76:1279-1289.
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113. Rydlewicz A, Simpson JA, Taylor FU, et al. The effect of folic acid supplementation on plasma homocysteine in an elderly population. QJM 2002; 95:27-35.
114. Daly S, Mills JL, Molloy AM, et al. Low dose folic acid lowers plasma homocysteine levels in women of child bearing age: a double blind, randomized placebo controlled trial. QJM 2002; 95:733-740.
115. Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 2003; 77:658-662. This randomized controlled trial is the first to compare the homocysteine lowering effect of 100 μg folic acid with an equivalent amount of 5-methyl THF.
116. Litynski P, Loehrer F, Linder L, et al. Effect of low doses of 5-methyltetrahydrofolate and folic acid on plasma homocysteine in healthy subjects with or without the 677C→T polymorphism of methylenetetrahydrofolate reductase. Eur J Clin Invest 2002; 32:662-668. This interesting study describes similar effects of folic acid and 5-methyl THF in lowering homocysteine of MTHFR 677 CC and TT individuals; however more work is needed to confirm that 5-methyl THF is as effective as folic acid in TT individuals.
117. Fohr IP, Prinz-Langenohl R, Bronstrup A, et al. 5,10- Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr 2002; 75:275-282.
118. Ashfield-Watt PAL, Pullin CH, Whiting CH, et al. Methylenetetrahydrofolate reductase 677C→T genotype modulates homocysteine responses to a folate rich diet or a low-dose folic acid supplement: a randomized controlled trial. Am J Clin Nutr 2002; 76:180-186.
119. Cuskelly GJ, McNulty H, Scott JM. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects. Lancet 1996; 347:657-659.
120. Venn BJ, Mann JI, Williams SM, et al. Dietary counseling to increase natural folate intake: a randomized, placebo-controlled trial in free-living subjects to assess effects on serum folate and plasma total homocysteine. Am J Clin Nutr 2002; 76:758-765.
121. Bostom AG, Selhub J, Jacques PF, Rosenberg IH. Power shortage: clinical trials testing the 'homocysteine hypothesis' against a background of folic acid-fortified cereal grain flour. Ann Intern Med 2001; 135:133-137.
122. Rader JI. Folic acid fortification, folate status and plasma homocysteine. J Nutr 2002; 132:24663-24703. This is an excellent summary of the effects of the fortification strategy in the USA.
123. Quinlivan EP, Gregory JF III. Effect of food fortification on folic acid intake in the United States. Am J Clin Nutr 2003; 77:221-225. This study extrapolates data from intervention studies to actual increases in the average blood folate status of US citizens since fortification and concludes that folate intake is about twice the predicted level.
124. Quinlivan EP, McPartlin J, McNulty H, et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 2002; 359:227-228.
125. Kelly PJ, Shih VE, Kistler JP, et al. Low vitamin B6 but not homocyst(e)ine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification. Stroke 2003; 34:e51-e54. This small case-control study found a highly significant difference in vitamin B6 between recent stroke victims and controls.