Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study

European Journal of Clinical Nutrition volume 60, pages 614–622 (2006)Cite this article

Abstract

Background:

Reduction in total homocysteine (tHcy) may be clinically relevant in the prevention of cardiovascular disease (CVD) in the general population.

Objective:

To examine the effects of changes in various lifestyle habits and lifestyle related biological CVD risk markers on changes in tHcy in relation to MTHFR(C677T) genotype.

Design:

A 1 year follow-up study.

Setting:

Copenhagen County, Denmark.

Subjects:

Statistical analyses were based on a population-based sample of 915 men and women aged 30–60 years assessed to be at increased CVD risk at baseline and therefore offered lifestyle intervention and re-examination after one year.

Results:

None of the studied lifestyle changes – smoking, physical activity, dietary habits, and coffee, tea, and alcohol consumption – was significantly associated with changes in tHcy, either overall, or in any of the MTHFR genotype subgroups. In addition, changes in tHcy did not differ between participants randomized to low- and high-intensity lifestyle intervention. However, the MTHFR TT genotype was associated with a significant decrease in tHcy compared with the CC/CT genotype in which an increase was observed. In addition, changes in tHcy were associated with changes in several of the biological CVD risk markers: weight, total cholesterol, HDL cholesterol, LDL cholesterol and systolic blood pressure.

Conclusions:

Our results indicate that tHcy may not be reduced by lifestyle changes; additionally, they suggest that tHcy may be related to biological CVD risk markers through a lifestyle independent pathway.

Sponsorships:

Danish Heart Foundation, Danish Medical Research Council, Danish Centre for Evaluation and Health Technology Assessment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  • Beulens JW, Sierksma A, Schaafsma G, Kok FJ, Struys EA, Jakobs C et al. (2005). Kinetics of homocysteine metabolism after moderate alcohol consumption. Alcohol Clin Exp Res 29, 739–745.

    Article  CAS  Google Scholar 

  • Bleich S, Bleich K, Kropp S, Bittermann HJ, Degner D, Sperling W et al. (2001). Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the ‘French Paradox’? Alcohol Alcohol 36, 189–192.

    Article  CAS  Google Scholar 

  • Boushey CJ, Beresford SA, Omenn GS, Motulsky AG (1995). A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274, 1049–1057.

    Article  CAS  Google Scholar 

  • Brown KS, Kluijtmans LA, Young IS, Murray L, McMaster D, Woodside JV et al. (2004). The 5,10-methylenetetrahydrofolate reductase C677T polymorphism interacts with smoking to increase homocysteine. Atherosclerosis 174, 315–322.

    Article  CAS  Google Scholar 

  • Clarke R, Lewington S, Donald A, Johnston C, Refsum H, Stratton I et al. (2001). Underestimation of the importance of homocysteine as a risk factor for cardiovascular disease in epidemiological studies. J Cardiovasc Risk 8, 363–369.

    Article  CAS  Google Scholar 

  • Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M et al. (1999). Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 150, 341–353.

    Article  CAS  Google Scholar 

  • Cook RD (1979). Influential observations in linear-regression. J Am Statist Assoc 74, 169–174.

    Article  Google Scholar 

  • De Bree A, Verschuren WM, Blom HJ (2001a). Biological cardiovascular risk factors and plasma homocysteine levels in the general Dutch population. Atherosclerosis 154, 513–514.

    Article  CAS  Google Scholar 

  • De Bree A, Verschuren WM, Blom HJ, Kromhout D (2001b). Lifestyle factors and plasma homocysteine concentrations in a general population sample. Am J Epidemiol 154, 150–154.

    Article  CAS  Google Scholar 

  • Dedoussis GV, Panagiotakos DB, Chrysohoou C, Pitsavos C, Zampelas A, Choumerianou D et al. (2004). Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C – >T mutation on homocysteine concentrations in healthy adults: the ATTICA Study. Am J Clin Nutr 80, 849–854.

    Article  CAS  Google Scholar 

  • Duncan GE, Perri MG, Anton SD, Limacher MC, Martin AD, Lowenthal DT et al. (2004). Effects of exercise on emerging and traditional cardiovascular risk factors. Prev Med 39, 894–902.

    Article  Google Scholar 

  • El Khairy L, Ueland PM, Nygard O, Refsum H, Vollset SE (1999). Lifestyle and cardiovascular disease risk factors as determinants of total cysteine in plasma: the Hordaland Homocysteine Study. Am J Clin Nutr 70, 1016–1024.

    Article  CAS  Google Scholar 

  • Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB (2002). Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case- control studies. Int J Epidemiol 31, 59–70.

    Article  Google Scholar 

  • Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10, 111–113.

    Article  CAS  Google Scholar 

  • Henning BF, Tepel M, Riezler R, Gillessen A, Doberauer C (1998). Vitamin supplementation during weight reduction – favourable effect on homocysteine metabolism. Res Exp Med (Berlin) 198, 37–42.

    Article  CAS  Google Scholar 

  • Homocysteine Lowering Trialists' Collaboration (1998). Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316, 894–898.

    Article  Google Scholar 

  • Husemoen LL, Thomsen TF, Fenger M, Jorgensen HL, Jorgensen T (2003). Contribution of thermolabile methylenetetrahydrofolate reductase variant to total plasma homocysteine levels in healthy men and women. Inter99 (2). Genet Epidemiol 24, 322–330.

    Article  Google Scholar 

  • Husemoen LL, Thomsen TF, Fenger M, Jorgensen T (2004). Effect of lifestyle factors on plasma total homocysteine concentrations in relation to MTHFR(C677T) genotype. Inter99 (7). Eur J Clin Nutr 58, 1142–1150.

    Article  CAS  Google Scholar 

  • Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J (2000). Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin Chem 46, 1065–1071.

    CAS  PubMed  Google Scholar 

  • Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH et al. (1996). Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93, 7–9.

    Article  CAS  Google Scholar 

  • Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J (2001). Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73, 613–621.

    Article  CAS  Google Scholar 

  • Jacques PF, Kalmbach R, Bagley PJ, Russo GT, Rogers G, Wilson PW et al. (2002). The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. J Nutr 132, 283–288.

    Article  CAS  Google Scholar 

  • Jorgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger C (2003). A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur J Cardiovasc Prev Rehabil 10, 377–386.

    Article  Google Scholar 

  • Jorgensen T, Borch-Johnsen K, Thomsen TF, Pisinger C, Ibsen H (2004). A randomized non-pharmacological intervention study for prevention of ischemic heart disease – Inter99. Eur Heart J 25, 122.

    Google Scholar 

  • Lim U, Cassano PA (2002). Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol 156, 1105–1113.

    Article  Google Scholar 

  • Mangoni AA, Sherwood RA, Swift CG, Jackson SH (2002). Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med 252, 497–503.

    Article  CAS  Google Scholar 

  • Marill KA (2004). Advanced statistics: linear regression, part II: multiple linear regression. Acad Emerg Med 11, 94–102.

    Article  Google Scholar 

  • Meleady R, Ueland PM, Blom H, Whitehead AS, Refsum H, Daly LE et al. (2003). Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project. Am J Clin Nutr 77, 63–70.

    Article  CAS  Google Scholar 

  • Nurk E, Tell GS, Vollset SE, Nygard O, Refsum H, Nilsen RM et al. (2004). Changes in lifestyle and plasma total homocysteine: the Hordaland Homocysteine Study. Am J Clin Nutr 79, 812–819.

    Article  CAS  Google Scholar 

  • Nygard O, Refsum H, Ueland PM, Stensvold I, Nordrehaug JE, Kvale G et al. (1997). Coffee consumption and plasma total homocysteine: the Hordaland Homocysteine Study. Am J Clin Nutr 65, 136–143.

    Article  CAS  Google Scholar 

  • Nygard O, Refsum H, Ueland PM, Vollset SE (1998). Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr 67, 263–270.

    Article  CAS  Google Scholar 

  • Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE et al. (1995). Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 274, 1526–1533.

    Article  CAS  Google Scholar 

  • O K, Lynn EG, Chung YH, Siow YL, Man RY, Choy PC (1998). Homocysteine stimulates the production and secretion of cholesterol in hepatic cells. Biochim Biophys Acta 1393, 317–324.

    Article  CAS  Google Scholar 

  • Panagiotakos DB, Pitsavos C, Zeimbekis A, Chrysohoou C, Stefanadis C (2005). The association between lifestyle-related factors and plasma homocysteine levels in healthy individuals from the ‘ATTICA’ Study. Int J Cardiol 98, 471–477.

    Article  Google Scholar 

  • Rasmussen LB, Ovesen L, Bulow I, Knudsen N, Laurberg P, Perrild H (2000). Folate intake, lifestyle factors, and homocysteine concentrations in younger and older women. Am J Clin Nutr 72, 1156–1163.

    Article  CAS  Google Scholar 

  • Russo GT, Friso S, Jacques PF, Rogers G, Cucinotta D, Wilson PW et al. (2003). Age and gender affect the relation between methylenetetrahydrofolate reductase C677T genotype and fasting plasma homocysteine concentrations in the Framingham Offspring Study Cohort. J Nutr 133, 3416–3421.

    Article  CAS  Google Scholar 

  • Saw SM, Yuan JM, Ong CN, Arakawa K, Lee HP, Coetzee GA et al. (2001). Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore. Am J Clin Nutr 73, 232–239.

    Article  CAS  Google Scholar 

  • Spotila LD, Jacques PF, Berger PB, Ballman KV, Ellison RC, Rozen R (2003). Age dependence of the influence of methylenetetrahydrofolate reductase genotype on plasma homocysteine level. Am J Epidemiol 158, 871–877.

    Article  Google Scholar 

  • Stehouwer CD, van Guldener C (2003). Does homocysteine cause hypertension? Clin Chem Lab Med 41, 1408–1411.

    Article  CAS  Google Scholar 

  • Stein JH, Bushara M, Bushara K, McBride PE, Jorenby DE, Fiore MC (2002). Smoking cessation, but not smoking reduction, reduces plasma homocysteine levels. Clin Cardiol 25, 23–26.

    Article  Google Scholar 

  • Strandhagen E, Landaas S, Thelle DS (2003). Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled study. Eur J Clin Nutr 57, 1411–1417.

    Article  CAS  Google Scholar 

  • Strandhagen E, Zetterberg H, Aires N, Palmer M, Rymo L, Blennow K et al. (2004). The methylenetetrahydrofolate reductase C677T polymorphism is a major determinant of coffee-induced increase of plasma homocysteine: a randomized placebo controlled study. Int J Mol Med 13, 811–815.

    CAS  PubMed  Google Scholar 

  • Thomsen TF, Davidsen M, Ibsen H, Jorgensen T, Jensen G, Borch-Johnsen K (2001). A new method for CHD prediction and prevention based on regional risk scores and randomized clinical trials; PRECARD and the Copenhagen Risk Score. J Cardiovasc Risk 8, 291–297.

    Article  CAS  Google Scholar 

  • Tonstad S, Urdal P (2002). Does short-term smoking cessation reduce plasma total homocysteine concentrations? Scand J Clin Lab Invest 62, 279–284.

    Article  CAS  Google Scholar 

  • van der Gaag MS, Ubbink JB, Sillanaukee P, Nikkari S, Hendriks HF (2000). Effect of consumption of red wine, spirits, and beer on serum homocysteine. Lancet 355, 1522.

    Article  CAS  Google Scholar 

  • van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD (2001). Long-term homocysteine-lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: a 2-year, randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol 21, 2072–2079.

    Article  CAS  Google Scholar 

  • van Guldener C, Nanayakkara PW, Stehouwer CD (2003). Homocysteine and blood pressure. Curr Hypertens Rep 5, 26–31.

    Article  Google Scholar 

  • Vickers AJ, Altman DG (2001). Statistics notes: analysing controlled trials with baseline and follow up measurements. BMJ 323, 1123–1124.

    Article  CAS  Google Scholar 

  • Woo CW, Siow YL, Pierce GN, Choy PC, Minuk GY, Mymin D et al. (2005). Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors. Am J Physiol Endocrinol Metab 288, 1002–1010.

    Article  Google Scholar 

  • Wright M, Francis K, Cornwell P (1998). Effect of acute exercise on plasma homocysteine. J Sports Med Phys Fitness 38, 262–265.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The Danish Heart Foundation, the Danish Medical Research Council, and the Danish Centre for Evaluation and Health Technology assessment financially supported this study.

Author information

Authors and Affiliations

  1. Research Centre for Prevention and Health, Copenhagen County, Glostrup, Denmark

    L L N Husemoen, T F Thomsen & T Jørgensen

  2. Department of Clinical Biochemistry, Hvidovre University Hospital, Hvidovre, Denmark

    M Fenger

Authors
  1. L L N Husemoen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T F Thomsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Fenger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L L N Husemoen.

Additional information

Guarantor: LLN Husemoen.

Contributors: LLNH contributed to statistical analysis, interpretation of results and writing of the manuscript. TFT contributed to study design, interpretation of results and revision of the manuscript. MF contributed to interpretation of results and revision of the manuscript. TJ contributed to study design, interpretation of results, and revision of the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Husemoen, L., Thomsen, T., Fenger, M. et al. Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study. Eur J Clin Nutr 60, 614–622 (2006). https://doi.org/10.1038/sj.ejcn.1602360

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ejcn.1602360

Keywords

This article is cited by

Search

Advanced search

Quick links