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Letters to the Editor |
Oregon Health Sciences University School of Medicine Department of Medicine Division of Endocrinology, Diabetes and Clinical Nutrition, L465 3181 SW Sam Jackson Park Road Portland, OR 97201-3098
Dear Sir:
Woodside et al (1) recently published an interesting study of the effects of folic acid and vitamins B-6 and B-12 on total plasma homocysteine (tHcy) concentrations in 132 men stratified for the common heat-labile polymorphism [a C-to-T substitution at nucleotide 677 (C677T)] in the gene for methylenetetrahydrofolate reductase (MTHFR). On the basis of results from a subgroup of 50 subjects in this study, the authors concluded that persons who are homozygous (T/T) for the polymorphism are less responsive to the effects of folic acid and B-vitamin supplementation than persons homozygous for the nonthermolabile allele (C/C). They also hypothesized that doses of folic acid >1 mg/d may be required to reduce plasma tHcy concentrations in the T/T subgroup.
These results are in contrast with those from our previous studies of the effects of supplementation with 1 or 2 mg folic acid/d in 242 men and women classified by coronary artery disease status, multivitamin use, and the C677T MTHFR genotype (2). The results of our study, and those of studies by Jacques et al (3) and Deloughery et al (4), suggest that T/T homozygotes are more sensitive to the adverse tHcy-raising effects of reduced plasma folate concentrations. Moreover, our T/T subjects experienced much greater decreases in plasma tHcy concentrations after receiving 1 or 2 mg folic acid/d for 3 wk than did C/C subjects (2). Among subjects who were not previously taking multivitamins, the mean reductions in plasma tHcy concentrations were -20.9%, -13.1%, and -7.1% in persons with the T/T, C/T, and C/C genotypes, respectively (P = 0.019 for T/T compared with C/C; Figure 1
). The decreases in plasma tHcy concentrations were not significantly different for subjects receiving 1 compared with 2 mg folic acid/d. Subjects who were previously taking multivitamins experienced smaller decreases in plasma tHcy concentrations after folic acid supplementation, but the T/T homozygotes still showed a trend for greater responsiveness than the C/C or C/T subjects (changes in plasma tHcy concentrations: -10.2%, -3.3%, and -3.2% for T/T, C/T, and C/C genotypes, respectively; NS) (2). Geometric mean plasma tHcy concentrations among T/T, C/T, and C/C subjects were not significantly different after folic acid supplementation. Thus, although individuals with the T/T genotype had higher plasma tHcy concentrations at baseline, our results suggest that these individuals were more sensitive to the tHcy-lowering effects of folic acid supplementation. The reasons for the disparities among the results of these studies are unknown, but additional investigations, including further analyses of the data from Woodside et al, may help to elucidate possible contributory factors.
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REFERENCES
Department of Surgery University College London 67-73 Riding House Street London, W1P 7LD United Kingdom E-mail: j.woodside{at}ucl.ac.uk
School of Clinical Medicine The Queen's University of Belfast Grosvenor Road Belfast BT12 6BJ United Kingdom
Department of Biochemistry University of Berne Switzerland
Department of Genetics Trinity College Dublin 2 Ireland and
Department of Pathology Biotechnology Centre University College Dublin Ireland
Department of Pharmacology and Center for Experimental Therapeutics University of Pennsylvania School of Medicine Philadelphia, PA
Dear Sir:
We note with interest the findings of Malinow et al (1) that supplementation with either 1 or 2 mg folic acid/d was sufficient to reduce total plasma homocysteine (tHcy) concentrations in persons homozygous for the thermolabile methylenetetrahydrofolate reductase (MTHFR) allele (T/T) to concentrations seen in similarly supplemented persons homozygous for the nonthermolabile allele (C/C). As pointed out by Duell and Malinow, this result is in contrast with our observation that T/T homozygotes still had elevated tHcy concentrations compared with C/C homozygotes after an 8-wk period of daily supplementation with 1 mg folic acid (2). On the basis of our results, we consequently proposed that hyperhomocysteinemic T/T homozygotes may require a higher dose of folic acid than their peers with other MTHFR genotypes to achieve a given target homocysteine concentration.
The reason for the above disparity is unclear. The number of T/T homozygotes in our study, which was not designed primarily to analyze responses to folic acid in the context of genotype, was small. Nevertheless, our results may reflect an underlying differential responsiveness of the MTHFR T/T genotype in the Northern Ireland population. Cross-sectional studies published by Jacques et al (3), Deloughery et al (4), and our own group (5) showed that folate-replete persons have essentially similar (low) tHcy concentrations regardless of MTHFR genotype, whereas among those with low folate concentrations, T/T homozygotes tend to have higher tHcy concentrations. Thus, it seems likely that a folate threshold exists below which T/T homozygotes have higher tHcy concentrations than C/T heterozygotes or C/C homozygotes. This threshold is likely to be influenced by genetic, socioeconomic, environmental, and nutritional factors and will therefore differ between populations. There is also likely to be considerable interindividual variation, with some subjects being relatively unresponsive to folic acid supplementation. Indeed, Guttormsen et al (6) reported that some T/T homozygotes in the Norwegian population still have high homocysteine concentrations after long-term supplementation with 5 mg folic acid/d (6). In addition, in our study, we selected subjects in the top 30% of the tHcy range and it is therefore likely that our results were biased toward those who had additional tHcy-raising risk factors that do not respond to folic acid supplementation or that may interact differentially with folate status and MTHFR genotype.
Direct comparison between our study and that of Malinow et al (1) is difficult because the populations studied were small and differed considerably in age and sex distributions. Furthermore, our subjects were healthy with no overt disease, whereas 58% of those studied by Malinow et al had coronary heart disease.
It is clear from the different and sometimes contradictory findings with respect to disease risks associated with both elevated tHcy and the MTHFR T/T genotype that have been reported in many studies that the biological factors governing tHcy metabolism and pathogenicity are complex and may differ considerably between populations. Therefore, it is likely that additional, large dose-finding studies performed in well-characterized populations will be required to define both the precise role of folate status in determining tHcy concentrations and the genotype-specific effects that modulate the potential for folic acid supplementation to correct hyperhomocysteinemia.
FOOTNOTES
Editor's note: Kung et al chose not to respond to this letter.
REFERENCES
40 µmol/l). The Hordaland Homocysteine Study. J Clin Invest 1996;98:2174–83.[Medline]
This article has been cited by other articles:
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  C. Williams, B. A Kingwell, K. Burke, J. McPherson, and A. M Dart Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype Am. J. Clinical Nutrition, July 1, 2005; 82(1): 26 - 31. [Abstract] [Full Text] [PDF]
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