Mendelian randomisation study of the associations of vitamin b12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three danish population-based studies

Mendelian randomisation study of the associations of vitamin b12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three danish population-based studies

Play all audios:

Loading...

ABSTRACT BACKGROUND/OBJECTIVES: The aim was to examine the association of genetic risk scores (GRSs) of vitamin B12 and folate-associated variants with blood pressure and lipids. SUBJECTS/METHODS: The study included 12 532 adults from three population-based studies (Inter99, Health2006 and Dan-MONICA10) conducted in Denmark. GRSs were calculated by summarising the number of vitamin B12 and folate increasing alleles. Weighted GRSs were calculated as the sum of weights for each allele corresponding to genetic effects sizes. RESULTS: GRSs for serum vitamin B12 and folate were associated with serum vitamin B12 and folate, respectively. The β coefficients (95% confidence interval (CI), _P-_value) for regression of log-transformed serum B12/folate on the weighted GRSs were 0.57 (0.54, 0.61), _P_<0.001 and 0.85 (0.70, 1.01), _P_<0.01. No associations were observed between the vitamin B12 GRSs and any of the blood pressure and lipid-related outcomes in the combined analyses. Increasing number of folate increasing alleles was associated with increased high-density lipoprotein (HDL) cholesterol concentrations (β coefficient (95% CI, _P_-value) for regression of log-transformed HDL on the weighted GRSs, 0.081 (0.015, 0.148), _P_=0.017), but not with blood pressure, triglyceride, and low-density lipoprotein and total cholesterol levels. CONCLUSIONS: GRSs were not associated with blood pressure and lipid levels, except for an association between the GRS for folate and HDL cholesterol. Further studies are needed to determine whether a causal association between folate and HDL cholesterol exists. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS GENETICALLY DETERMINED CIRCULATING MICRONUTRIENTS AND THE RISK OF NONALCOHOLIC FATTY LIVER DISEASE Article Open access 11 January 2024 MENDELIAN RANDOMIZATION ON THE ASSOCIATION OF OBESITY WITH VITAMIN D: GUANGZHOU BIOBANK COHORT STUDY Article 08 November 2022 EFFECTS OF SELENIUM ON CORONARY ARTERY DISEASE, TYPE 2 DIABETES AND THEIR RISK FACTORS: A MENDELIAN RANDOMIZATION STUDY Article 07 April 2021 REFERENCES * Debreceni B, Debreceni L . The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. _Cardiovasc Ther_ 2014; 32: 130–138. Article  CAS  Google Scholar  * Rimm EB, Stampfer MJ . Folate and cardiovascular disease: one size does not fit all. _Lancet_ 2011; 378: 544–546. Article  Google Scholar  * Selhub J . Homocysteine metabolism. _Annu Rev Nutr_ 1999; 19: 217–246. Article  CAS  Google Scholar  * Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. _JAMA_ 2002; 288: 2015–2021. Article  Google Scholar  * Wald DS, Law M, Morris JK . Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. _BMJ_ 2002; 325: 1202. Article  Google Scholar  * de Bree A, Verschuren WM, Blom HJ . Biological cardiovascular risk factors and plasma homocysteine levels in the general Dutch population. _Atherosclerosis_ 2001; 154: 513–514. Article  CAS  Google Scholar  * Husemoen LL, Linneberg A, Fenger M, Thuesen BH, Jorgensen T . 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_ 2009; 63: 1233–1240. Article  CAS  Google Scholar  * Husemoen LL, Skaaby T, Jorgensen T, Thuesen BH, Fenger M, Grarup N _et al_. MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification. _Eur J Nutr_ 2014. * Husemoen LL, Thomsen TF, Fenger M, Jorgensen T . Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study. _Eur J Clin Nutr_ 2006; 60: 614–622. Article  CAS  Google Scholar  * Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE _et al_. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. _JAMA_ 1995; 274: 1526–1533. Article  CAS  Google Scholar  * Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. _BMJ_ 1998; 316: 894–898. * Bazzano LA, He J, Ogden LG, Loria C, Vupputuri S, Myers L _et al_. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. _Stroke_ 2002; 33: 1183–1188. Article  CAS  Google Scholar  * Giles WH, Kittner SJ, Anda RF, Croft JB, Casper ML . Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study. _Stroke_ 1995; 26: 1166–1170. Article  CAS  Google Scholar  * Imamura A, Murakami R, Takahashi R, Cheng XW, Numaguchi Y, Murohara T _et al_. Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy nonsmokers. _Metabolism_ 2010; 59: 728–733. Article  CAS  Google Scholar  * Voutilainen S, Lakka TA, Porkkala-Sarataho E, Rissanen T, Kaplan GA, Salonen JT . Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. _Eur J Clin Nutr_ 2000; 54: 424–428. Article  CAS  Google Scholar  * Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT . Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease Risk Factor Study. _Circulation_ 2001; 103: 2674–2680. Article  CAS  Google Scholar  * Voutilainen S, Virtanen JK, Rissanen TH, Alfthan G, Laukkanen J, Nyyssonen K _et al_. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. _Am J Clin Nutr_ 2004; 80: 317–323. Article  CAS  Google Scholar  * Antoniades C, Antonopoulos AS, Tousoulis D, Marinou K, Stefanadis C . Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials. _Eur Heart J_ 2009; 30: 6–15. Article  CAS  Google Scholar  * Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H _et al_. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. _Circulation_ 2006; 113: 1335–1343. Article  Google Scholar  * Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E _et al_. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. _JAMA_ 2008; 299: 2027–2036. Article  CAS  Google Scholar  * Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K _et al_. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. _JAMA_ 2010; 303: 2486–2494. Article  CAS  Google Scholar  * Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T _et al_. Homocysteine lowering and cardiovascular events after acute myocardial infarction. _N Engl J Med_ 2006; 354: 1578–1588. Article  CAS  Google Scholar  * Ebbing M, Bleie O, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE _et al_. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. _JAMA_ 2008; 300: 795–804. Article  CAS  Google Scholar  * Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD _et al_. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. _JAMA_ 2007; 298: 1163–1170. Article  CAS  Google Scholar  * Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M _et al_. Homocysteine lowering with folic acid and B vitamins in vascular disease. _N Engl J Med_ 2006; 354: 1567–1577. Article  CAS  Google Scholar  * Marti-Carvajal AJ, Sola I, Lathyris D . Homocysteine-lowering interventions for preventing cardiovascular events. _Cochrane Database Syst Rev_ 2015; 1: CD006612. PubMed  Google Scholar  * Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ _et al_. 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_ 2004; 291: 565–575. Article  CAS  Google Scholar  * Holmes MV, Newcombe P, Hubacek JA, Sofat R, Ricketts SL, Cooper J _et al_. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. _Lancet_ 2011; 378: 584–594. Article  CAS  Google Scholar  * Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E . Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. _Stroke_ 2009; 40: 1365–1372. Article  CAS  Google Scholar  * Spence JD, Bang H, Chambless LE, Stampfer MJ . Vitamin intervention for stroke prevention trial: an efficacy analysis. _Stroke_ 2005; 36: 2404–2409. Article  CAS  Google Scholar  * Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD . Homocysteine and stroke: evidence on a causal link from mendelian randomisation. _Lancet_ 2005; 365: 224–232. Article  CAS  Google Scholar  * Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG . MTHFR 677C—&gt;T polymorphism and risk of coronary heart disease: a meta-analysis. _JAMA_ 2002; 288: 2023–2031. Article  CAS  Google Scholar  * Lewis SJ, Ebrahim S, Davey SG . Meta-analysis of MTHFR 677C-&gt;T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? _BMJ_ 2005; 331: 1053. Article  CAS  Google Scholar  * Hersoug LG, Husemoen LL, Thomsen SF, Sigsgaard T, Thuesen BH, Linneberg A . Association of indoor air pollution with rhinitis symptoms, atopy and nitric oxide levels in exhaled air. _Int Arch Allergy Immunol_ 2010; 153: 403–412. Article  CAS  Google Scholar  * Jorgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger C . A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. _Eur J Cardiovasc Prev Rehabil_ 2003; 10: 377–386. Article  Google Scholar  * Husemoen LL, Skaaby T, Thuesen BH, Jorgensen T, Fenger RV, Linneberg A . Serum 25(OH)D and incident type 2 diabetes: a cohort study. _Eur J Clin Nutr_ 2012; 66: 1309–1314. Article  CAS  Google Scholar  * Husemoen LL, Jorgensen T, Borch-Johnsen K, Hansen T, Pedersen O, Linneberg A . The association of alcohol and alcohol metabolizing gene variants with diabetes and coronary heart disease risk factors in a white population. _PLoS One_ 2010; 5: e11735. Article  Google Scholar  * Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS, Steinthorsdottir V _et al_. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. _PLoS Genet_ 2013; 9: e1003530. Article  CAS  Google Scholar  * Burgess S, Thompson SG . Use of allele scores as instrumental variables for Mendelian randomization. _Int J Epidemiol_ 2013; 42: 1134–1144. Article  Google Scholar  * Husemoen LL, Thomsen TF, Fenger M, Jorgensen HL, Jorgensen T . Contribution of thermolabile methylenetetrahydrofolate reductase variant to total plasma homocysteine levels in healthy men and women. Inter99 (2). _Genet Epidemiol_ 2003; 24: 322–330. Article  Google Scholar  * Forman JP, Rimm EB, Stampfer MJ, Curhan GC . Folate intake and the risk of incident hypertension among US women. _JAMA_ 2005; 293: 320–329. Article  CAS  Google Scholar  * Xun P, Liu K, Loria CM, Bujnowski D, Shikany JM, Schreiner PJ _et al_. Folate intake and incidence of hypertension among American young adults: a 20-y follow-up study. _Am J Clin Nutr_ 2012; 95: 1023–1030. Article  CAS  Google Scholar  * Cagnacci A, Cannoletta M, Volpe A . High-dose short-term folate administration modifies ambulatory blood pressure in postmenopausal women. A placebo-controlled study. _Eur J Clin Nutr_ 2009; 63: 1266–1268. Article  CAS  Google Scholar  * Mangoni AA, Sherwood RA, Swift CG, Jackson SH . Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. _J Intern Med_ 2002; 252: 497–503. Article  CAS  Google Scholar  * van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD . 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_ 2001; 21: 2072–2079. Article  CAS  Google Scholar  * Wang L, Li H, Zhou Y, Jin L, Liu J . Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled trial in healthy Chinese elderly. _Eur J Nutr_ 2015; 54: 455–464. Article  CAS  Google Scholar  * Villa P, Perri C, Suriano R, Cucinelli F, Panunzi S, Ranieri M _et al_. L-folic acid supplementation in healthy postmenopausal women: effect on homocysteine and glycolipid metabolism. _J Clin Endocrinol Metab_ 2005; 90: 4622–4629. Article  CAS  Google Scholar  * Paradisi G, Cucinelli F, Mele MC, Barini A, Lanzone A, Caruso A . Endothelial function in post-menopausal women: effect of folic acid supplementation. _Hum Reprod_ 2004; 19: 1031–1035. Article  CAS  Google Scholar  * Tran-Dinh A, Diallo D, Delbosc S, Varela-Perez LM, Dang QB, Lapergue B _et al_. HDL and endothelial protection. _Br J Pharmacol_ 2013; 169: 493–511. Article  CAS  Google Scholar  * Ng DS, Wong NC, Hegele RA . HDL—is it too big to fail? _Nat Rev Endocrinol_ 2013; 9: 308–312. Article  CAS  Google Scholar  * Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K _et al_. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. _N Engl J Med_ 2011; 365: 2255–2267. Article  Google Scholar  * Ginsberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, Linz P _et al_. Effects of combination lipid therapy in type 2 diabetes mellitus. _N Engl J Med_ 2010; 362: 1563–1574. Article  Google Scholar  * Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK _et al_. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. _Lancet_ 2012; 380: 572–580. Article  CAS  Google Scholar  * Davey SG, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? _Int J Epidemiol_ 2003; 32: 1–22. Article  Google Scholar  Download references ACKNOWLEDGEMENTS The present study was supported by grants from the Health Insurance Foundation (grant No. 2010 B 131), the Danish Agency for Science Technology and Innovation (grant No. 2101-06-0065), the Lundbeck Foundation Center for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp; http://www.lucamp.org) and The Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent research centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk). Tea Skaaby was supported by a grant from the Lundbeck Foundation (Grant number R165-2013-15410). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Research Centre for Prevention and Health, The Capital Region of Denmark, Glostrup University Hospital, Glostrup, Denmark L L N Husemoen, T Skaaby, B H Thuesen & A Linneberg * The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark N Grarup, C H Sandholt, T Hansen & O Pedersen * University of Southern Denmark, Odense, Denmark T Hansen * University of Copenhagen, Copenhagen, Denmark A Linneberg * Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Copenhagen, Denmark A Linneberg Authors * L L N Husemoen View author publications You can also search for this author inPubMed Google Scholar * T Skaaby View author publications You can also search for this author inPubMed Google Scholar * B H Thuesen View author publications You can also search for this author inPubMed Google Scholar * N Grarup View author publications You can also search for this author inPubMed Google Scholar * C H Sandholt View author publications You can also search for this author inPubMed Google Scholar * T Hansen View author publications You can also search for this author inPubMed Google Scholar * O Pedersen View author publications You can also search for this author inPubMed Google Scholar * A Linneberg View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to L L N Husemoen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1 (DOC 33 KB) SUPPLEMENTARY TABLE 2 (DOC 57 KB) SUPPLEMENTARY TABLE 3 (DOC 56 KB) SUPPLEMENTARY TABLE 4 (DOC 31 KB) SUPPLEMENTARY TABLE 5 (DOC 30 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Husemoen, L., Skaaby, T., Thuesen, B. _et al._ Mendelian randomisation study of the associations of vitamin B12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three Danish population-based studies. _Eur J Clin Nutr_ 70, 613–619 (2016). https://doi.org/10.1038/ejcn.2016.5 Download citation * Received: 04 May 2015 * Revised: 28 December 2015 * Accepted: 27 January 2016 * Published: 24 February 2016 * Issue Date: May 2016 * DOI: https://doi.org/10.1038/ejcn.2016.5 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative

ABSTRACT BACKGROUND/OBJECTIVES: The aim was to examine the association of genetic risk scores (GRSs) of vitamin B12 and folate-associated variants with blood pressure and lipids.


SUBJECTS/METHODS: The study included 12 532 adults from three population-based studies (Inter99, Health2006 and Dan-MONICA10) conducted in Denmark. GRSs were calculated by summarising the


number of vitamin B12 and folate increasing alleles. Weighted GRSs were calculated as the sum of weights for each allele corresponding to genetic effects sizes. RESULTS: GRSs for serum


vitamin B12 and folate were associated with serum vitamin B12 and folate, respectively. The β coefficients (95% confidence interval (CI), _P-_value) for regression of log-transformed serum


B12/folate on the weighted GRSs were 0.57 (0.54, 0.61), _P_<0.001 and 0.85 (0.70, 1.01), _P_<0.01. No associations were observed between the vitamin B12 GRSs and any of the blood


pressure and lipid-related outcomes in the combined analyses. Increasing number of folate increasing alleles was associated with increased high-density lipoprotein (HDL) cholesterol


concentrations (β coefficient (95% CI, _P_-value) for regression of log-transformed HDL on the weighted GRSs, 0.081 (0.015, 0.148), _P_=0.017), but not with blood pressure, triglyceride, and


low-density lipoprotein and total cholesterol levels. CONCLUSIONS: GRSs were not associated with blood pressure and lipid levels, except for an association between the GRS for folate and


HDL cholesterol. Further studies are needed to determine whether a causal association between folate and HDL cholesterol exists. Access through your institution Buy or subscribe This is a


preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per


year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated


during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS GENETICALLY


DETERMINED CIRCULATING MICRONUTRIENTS AND THE RISK OF NONALCOHOLIC FATTY LIVER DISEASE Article Open access 11 January 2024 MENDELIAN RANDOMIZATION ON THE ASSOCIATION OF OBESITY WITH VITAMIN


D: GUANGZHOU BIOBANK COHORT STUDY Article 08 November 2022 EFFECTS OF SELENIUM ON CORONARY ARTERY DISEASE, TYPE 2 DIABETES AND THEIR RISK FACTORS: A MENDELIAN RANDOMIZATION STUDY Article 07


April 2021 REFERENCES * Debreceni B, Debreceni L . The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. _Cardiovasc Ther_ 2014; 32: 130–138.


Article  CAS  Google Scholar  * Rimm EB, Stampfer MJ . Folate and cardiovascular disease: one size does not fit all. _Lancet_ 2011; 378: 544–546. Article  Google Scholar  * Selhub J .


Homocysteine metabolism. _Annu Rev Nutr_ 1999; 19: 217–246. Article  CAS  Google Scholar  * Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a


meta-analysis. _JAMA_ 2002; 288: 2015–2021. Article  Google Scholar  * Wald DS, Law M, Morris JK . Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. _BMJ_


2002; 325: 1202. Article  Google Scholar  * de Bree A, Verschuren WM, Blom HJ . Biological cardiovascular risk factors and plasma homocysteine levels in the general Dutch population.


_Atherosclerosis_ 2001; 154: 513–514. Article  CAS  Google Scholar  * Husemoen LL, Linneberg A, Fenger M, Thuesen BH, Jorgensen T . 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_ 2009; 63: 1233–1240. Article  CAS  Google Scholar  * Husemoen LL, Skaaby T, Jorgensen T, Thuesen


BH, Fenger M, Grarup N _et al_. MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification. _Eur J Nutr_ 2014. * Husemoen LL, Thomsen


TF, Fenger M, Jorgensen T . Changes in lifestyle and total homocysteine in relation to MTHFR(C677T) genotype: the Inter99 study. _Eur J Clin Nutr_ 2006; 60: 614–622. Article  CAS  Google


Scholar  * Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE _et al_. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. _JAMA_


1995; 274: 1526–1533. Article  CAS  Google Scholar  * Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists'


Collaboration. _BMJ_ 1998; 316: 894–898. * Bazzano LA, He J, Ogden LG, Loria C, Vupputuri S, Myers L _et al_. Dietary intake of folate and risk of stroke in US men and women: NHANES I


Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. _Stroke_ 2002; 33: 1183–1188. Article  CAS  Google Scholar  * Giles WH, Kittner SJ, Anda RF, Croft JB, Casper


ML . Serum folate and risk for ischemic stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study. _Stroke_ 1995; 26: 1166–1170. Article  CAS  Google


Scholar  * Imamura A, Murakami R, Takahashi R, Cheng XW, Numaguchi Y, Murohara T _et al_. Low folate levels may be an atherogenic factor regardless of homocysteine levels in young healthy


nonsmokers. _Metabolism_ 2010; 59: 728–733. Article  CAS  Google Scholar  * Voutilainen S, Lakka TA, Porkkala-Sarataho E, Rissanen T, Kaplan GA, Salonen JT . Low serum folate concentrations


are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. _Eur J Clin Nutr_ 2000; 54: 424–428. Article  CAS  Google Scholar  *


Voutilainen S, Rissanen TH, Virtanen J, Lakka TA, Salonen JT . Low dietary folate intake is associated with an excess incidence of acute coronary events: The Kuopio Ischemic Heart Disease


Risk Factor Study. _Circulation_ 2001; 103: 2674–2680. Article  CAS  Google Scholar  * Voutilainen S, Virtanen JK, Rissanen TH, Alfthan G, Laukkanen J, Nyyssonen K _et al_. Serum folate and


homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. _Am J Clin Nutr_ 2004; 80: 317–323. Article  CAS  Google Scholar  * Antoniades


C, Antonopoulos AS, Tousoulis D, Marinou K, Stefanadis C . Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials. _Eur Heart J_ 2009; 30: 6–15.


Article  CAS  Google Scholar  * Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H _et al_. Improvement in stroke mortality in Canada and the United States, 1990 to 2002.


_Circulation_ 2006; 113: 1335–1343. Article  Google Scholar  * Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E _et al_. Effect of folic acid and B vitamins on risk of


cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. _JAMA_ 2008; 299: 2027–2036. Article  CAS  Google Scholar  * Armitage JM,


Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K _et al_. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial


infarction survivors: a randomized trial. _JAMA_ 2010; 303: 2486–2494. Article  CAS  Google Scholar  * Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T _et al_. Homocysteine


lowering and cardiovascular events after acute myocardial infarction. _N Engl J Med_ 2006; 354: 1578–1588. Article  CAS  Google Scholar  * Ebbing M, Bleie O, Ueland PM, Nordrehaug JE,


Nilsen DW, Vollset SE _et al_. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. _JAMA_


2008; 300: 795–804. Article  CAS  Google Scholar  * Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD _et al_. Effect of homocysteine lowering on mortality and vascular


disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. _JAMA_ 2007; 298: 1163–1170. Article  CAS  Google Scholar  * Lonn E, Yusuf S, Arnold


MJ, Sheridan P, Pogue J, Micks M _et al_. Homocysteine lowering with folic acid and B vitamins in vascular disease. _N Engl J Med_ 2006; 354: 1567–1577. Article  CAS  Google Scholar  *


Marti-Carvajal AJ, Sola I, Lathyris D . Homocysteine-lowering interventions for preventing cardiovascular events. _Cochrane Database Syst Rev_ 2015; 1: CD006612. PubMed  Google Scholar  *


Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ _et al_. 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_ 2004; 291: 565–575. Article  CAS  Google Scholar  * Holmes MV, Newcombe P, Hubacek JA, Sofat


R, Ricketts SL, Cooper J _et al_. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic


studies and randomised trials. _Lancet_ 2011; 378: 584–594. Article  CAS  Google Scholar  * Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E . Homocysteine-lowering therapy and stroke risk,


severity, and disability: additional findings from the HOPE 2 trial. _Stroke_ 2009; 40: 1365–1372. Article  CAS  Google Scholar  * Spence JD, Bang H, Chambless LE, Stampfer MJ . Vitamin


intervention for stroke prevention trial: an efficacy analysis. _Stroke_ 2005; 36: 2404–2409. Article  CAS  Google Scholar  * Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD .


Homocysteine and stroke: evidence on a causal link from mendelian randomisation. _Lancet_ 2005; 365: 224–232. Article  CAS  Google Scholar  * Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ,


Schouten EG . MTHFR 677C—&gt;T polymorphism and risk of coronary heart disease: a meta-analysis. _JAMA_ 2002; 288: 2023–2031. Article  CAS  Google Scholar  * Lewis SJ, Ebrahim S, Davey


SG . Meta-analysis of MTHFR 677C-&gt;T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? _BMJ_


2005; 331: 1053. Article  CAS  Google Scholar  * Hersoug LG, Husemoen LL, Thomsen SF, Sigsgaard T, Thuesen BH, Linneberg A . Association of indoor air pollution with rhinitis symptoms, atopy


and nitric oxide levels in exhaled air. _Int Arch Allergy Immunol_ 2010; 153: 403–412. Article  CAS  Google Scholar  * Jorgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger


C . A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. _Eur J Cardiovasc Prev Rehabil_ 2003; 10: 377–386. Article 


Google Scholar  * Husemoen LL, Skaaby T, Thuesen BH, Jorgensen T, Fenger RV, Linneberg A . Serum 25(OH)D and incident type 2 diabetes: a cohort study. _Eur J Clin Nutr_ 2012; 66: 1309–1314.


Article  CAS  Google Scholar  * Husemoen LL, Jorgensen T, Borch-Johnsen K, Hansen T, Pedersen O, Linneberg A . The association of alcohol and alcohol metabolizing gene variants with diabetes


and coronary heart disease risk factors in a white population. _PLoS One_ 2010; 5: e11735. Article  Google Scholar  * Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS,


Steinthorsdottir V _et al_. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. _PLoS Genet_ 2013; 9: e1003530. Article  CAS  Google


Scholar  * Burgess S, Thompson SG . Use of allele scores as instrumental variables for Mendelian randomization. _Int J Epidemiol_ 2013; 42: 1134–1144. Article  Google Scholar  * Husemoen LL,


Thomsen TF, Fenger M, Jorgensen HL, Jorgensen T . Contribution of thermolabile methylenetetrahydrofolate reductase variant to total plasma homocysteine levels in healthy men and women.


Inter99 (2). _Genet Epidemiol_ 2003; 24: 322–330. Article  Google Scholar  * Forman JP, Rimm EB, Stampfer MJ, Curhan GC . Folate intake and the risk of incident hypertension among US women.


_JAMA_ 2005; 293: 320–329. Article  CAS  Google Scholar  * Xun P, Liu K, Loria CM, Bujnowski D, Shikany JM, Schreiner PJ _et al_. Folate intake and incidence of hypertension among American


young adults: a 20-y follow-up study. _Am J Clin Nutr_ 2012; 95: 1023–1030. Article  CAS  Google Scholar  * Cagnacci A, Cannoletta M, Volpe A . High-dose short-term folate administration


modifies ambulatory blood pressure in postmenopausal women. A placebo-controlled study. _Eur J Clin Nutr_ 2009; 63: 1266–1268. Article  CAS  Google Scholar  * Mangoni AA, Sherwood RA, Swift


CG, Jackson SH . Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. _J Intern Med_ 2002; 252: 497–503. Article  CAS  Google


Scholar  * van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD . 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_ 2001;


21: 2072–2079. Article  CAS  Google Scholar  * Wang L, Li H, Zhou Y, Jin L, Liu J . Low-dose B vitamins supplementation ameliorates cardiovascular risk: a double-blind randomized controlled


trial in healthy Chinese elderly. _Eur J Nutr_ 2015; 54: 455–464. Article  CAS  Google Scholar  * Villa P, Perri C, Suriano R, Cucinelli F, Panunzi S, Ranieri M _et al_. L-folic acid


supplementation in healthy postmenopausal women: effect on homocysteine and glycolipid metabolism. _J Clin Endocrinol Metab_ 2005; 90: 4622–4629. Article  CAS  Google Scholar  * Paradisi G,


Cucinelli F, Mele MC, Barini A, Lanzone A, Caruso A . Endothelial function in post-menopausal women: effect of folic acid supplementation. _Hum Reprod_ 2004; 19: 1031–1035. Article  CAS 


Google Scholar  * Tran-Dinh A, Diallo D, Delbosc S, Varela-Perez LM, Dang QB, Lapergue B _et al_. HDL and endothelial protection. _Br J Pharmacol_ 2013; 169: 493–511. Article  CAS  Google


Scholar  * Ng DS, Wong NC, Hegele RA . HDL—is it too big to fail? _Nat Rev Endocrinol_ 2013; 9: 308–312. Article  CAS  Google Scholar  * Boden WE, Probstfield JL, Anderson T, Chaitman BR,


Desvignes-Nickens P, Koprowicz K _et al_. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. _N Engl J Med_ 2011; 365: 2255–2267. Article  Google Scholar


  * Ginsberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, Linz P _et al_. Effects of combination lipid therapy in type 2 diabetes mellitus. _N Engl J Med_ 2010; 362: 1563–1574. Article


  Google Scholar  * Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK _et al_. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian


randomisation study. _Lancet_ 2012; 380: 572–580. Article  CAS  Google Scholar  * Davey SG, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to


understanding environmental determinants of disease? _Int J Epidemiol_ 2003; 32: 1–22. Article  Google Scholar  Download references ACKNOWLEDGEMENTS The present study was supported by grants


from the Health Insurance Foundation (grant No. 2010 B 131), the Danish Agency for Science Technology and Innovation (grant No. 2101-06-0065), the Lundbeck Foundation Center for Applied


Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp; http://www.lucamp.org) and The Novo Nordisk Foundation Center for Basic Metabolic Research, which is an


independent research centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk). Tea Skaaby was supported


by a grant from the Lundbeck Foundation (Grant number R165-2013-15410). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Research Centre for Prevention and Health, The Capital Region of


Denmark, Glostrup University Hospital, Glostrup, Denmark L L N Husemoen, T Skaaby, B H Thuesen & A Linneberg * The Novo Nordisk Foundation Center for Basic Metabolic Research, University


of Copenhagen, Copenhagen, Denmark N Grarup, C H Sandholt, T Hansen & O Pedersen * University of Southern Denmark, Odense, Denmark T Hansen * University of Copenhagen, Copenhagen,


Denmark A Linneberg * Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Copenhagen, Denmark A Linneberg Authors * L L N Husemoen View author publications You can also


search for this author inPubMed Google Scholar * T Skaaby View author publications You can also search for this author inPubMed Google Scholar * B H Thuesen View author publications You can


also search for this author inPubMed Google Scholar * N Grarup View author publications You can also search for this author inPubMed Google Scholar * C H Sandholt View author publications


You can also search for this author inPubMed Google Scholar * T Hansen View author publications You can also search for this author inPubMed Google Scholar * O Pedersen View author


publications You can also search for this author inPubMed Google Scholar * A Linneberg View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING


AUTHOR Correspondence to L L N Husemoen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies


this paper on European Journal of Clinical Nutrition website SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1 (DOC 33 KB) SUPPLEMENTARY TABLE 2 (DOC 57 KB) SUPPLEMENTARY TABLE 3 (DOC 56 KB)


SUPPLEMENTARY TABLE 4 (DOC 31 KB) SUPPLEMENTARY TABLE 5 (DOC 30 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Husemoen, L., Skaaby, T., Thuesen, B.


_et al._ Mendelian randomisation study of the associations of vitamin B12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three Danish population-based


studies. _Eur J Clin Nutr_ 70, 613–619 (2016). https://doi.org/10.1038/ejcn.2016.5 Download citation * Received: 04 May 2015 * Revised: 28 December 2015 * Accepted: 27 January 2016 *


Published: 24 February 2016 * Issue Date: May 2016 * DOI: https://doi.org/10.1038/ejcn.2016.5 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content:


Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative