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Changes in lifestyle, biological risk factors and total homocysteine in relation to MTHFR C677T genotype: a 5-year follow-up study

European Journal of Clinical Nutrition volume 63, pages 1233–1240 (2009)Cite this article

Abstract

Background/Objectives:

Total homocysteine (tHcy) has been associated with increased risk of several diseases in the general population. It is not clear whether these associations are causal. A less healthy lifestyle as well as a less favorable biological risk factor profile have been related to increased tHcy in cross-sectional studies. In addition, the methylenetetrahydrofolate reductase (MTHFR) C677T gene variant is an important determinant of elevated tHcy. The main objective of the study was to examine the effect of changes in biological risk factors and lifestyle on tHcy in relation to MTHFR C677T genotype.

Subjects/Methods:

The study is a population-based study including 1805 men and women aged 30–60 years participating in a health examination at baseline (1999–2001) and at a 5-year follow-up examination.

Results:

Changes in tHcy were not associated with changes in dietary habits, physical activity, smoking status, coffee, tea, total alcohol or wine consumption. An inverse relationship was observed between changes in tHcy and changes in the intake of beer in TT individuals but not in CC/CT individuals (Pinteraction=0.01). In addition, changes in tHcy were positively associated with changes in several biological risk factors, such as waist circumference, diastolic blood pressure, total cholesterol and LDL cholesterol (P<0.01). The association between waist circumference and MTHFR genotype seemed stronger in TT individuals than in CC/CT individuals (Pinteraction=0.03).

Conclusions:

tHcy was not influenced by lifestyle changes except for the inverse association between beer consumption and tHcy observed in TT individuals. This suggests that tHcy is not a mediator in the causal pathway between lifestyle and lifestyle-related diseases such as cardiovascular disease in accordance with results of recent randomized trials. However, tHcy was related to changes in several biological risk factors, suggesting that tHcy may be a good predictor or marker of disease.

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References

  • Aadahl M, von Huth Smith L, Pisinger C, Toft U, Glumer C, Borch-Johnsen K et al. (2009). Five-year change in physical activity is associated with changes in cardiovascular disease risk factors. The inter99 study. Prev Med 48, 326–331.

    Article  CAS  Google Scholar 

  • 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 

  • Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T et al. (2006). Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 354, 1578–1588.

    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 

  • 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 

  • Duthie SJ, Whalley LJ, Collins AR, Leaper S, Berger K, Deary IJ (2002). Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 75, 908–913.

    Article  CAS  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 

  • Elshorbagy AK, Nurk E, Gjesdal CG, Tell GS, Ueland PM, Nygard O et al. (2008). Homocysteine, cysteine, and body composition in the Hordaland Homocysteine Study: does cysteine link amino acid and lipid metabolism? Am J Clin Nutr 88, 738–746.

    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 

  • Homocysteine Lowering Trialists′ Collaboration (1998). Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists′ Collaboration. 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 

  • Husemoen LL, Thomsen TF, Fenger M, Jorgensen T (2006). Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study. Eur J Clin Nutr 60, 614–622.

    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 

  • Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M et al. (2006). Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354, 1567–1577.

    Article  CAS  Google Scholar 

  • McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE et al. (2004). Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350, 2042–2049.

    Article  CAS  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 

  • 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 

  • 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 

  • Schmölker L, Fagerstrom K (2000). Gram tobacco 2000. Personal communication.

  • 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, 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 

  • Toft U, Kristoffersen LH, Lau C, Borch-Johnsen K, Jorgensen T (2007). The Dietary Quality Score: validation and association with cardiovascular risk factors: the Inter99 study. Eur J Clin Nutr 61, 270–278.

    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 

  • Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ et al. (2004). Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291, 565–575.

    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 

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

    Article  CAS  Google Scholar 

  • Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK et al. (2000). Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr 71, 962–968.

    Article  CAS  Google Scholar 

  • von Huth SL, Borch-Johnsen K, Jorgensen T (2007). Commuting physical activity is favourably associated with biological risk factors for cardiovascular disease. Eur J Epidemiol 22, 771–779.

    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 

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Acknowledgements

We thank the participants, the Steering Committee (Torben Jørgensen (principal investigator), Knut Borch-johnsen (co-principal investigator), and Charlotta Pisinger), and all the members of the Inter99 staff at the Research Centre for Prevention and Health, Glostrup, Denmark and the Steno Diabetes Center, Gentofte, Denmark

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Authors and Affiliations

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

    L L N Husemoen, A Linneberg, B H Thuesen & T Jørgensen

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

    M Fenger

Authors
  1. L L N Husemoen
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  2. A Linneberg
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  3. M Fenger
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  4. B H Thuesen
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  5. T Jørgensen
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Corresponding author

Correspondence to L L N Husemoen.

Additional information

Contributors: LLNH, TJ and AL contributed to the development of hypothesis and study design. TJ was the principal investigator of the inter99 study and responsible for data collection. LLNH performed the genotype analyses in collaboration with MF. LLNH and AL performed the statistical analyses. LLNH wrote the first draft and coordinated the completion of the paper. AL, TJ, MF and BHT contributed to the interpretation of results, the revision of the paper and have approved the final version of the paper.

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Husemoen, L., Linneberg, A., Fenger, M. et al. Changes in lifestyle, biological risk factors and total homocysteine in relation to MTHFR C677T genotype: a 5-year follow-up study. Eur J Clin Nutr 63, 1233–1240 (2009). https://doi.org/10.1038/ejcn.2009.59

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