Homocysteine-reducing B Vitamins and Ischemic Heart Disease: a Separate-sample Mendelian Randomization Analysis

Overview

Journal Eur J Clin Nutr

Specialty Nutritional Sciences

Date 2016 Dec 1

PMID 27901035

Citations 8

Authors

J V Zhao

C M Schooling

Affiliations

Soon will be listed here.

Abstract

Background/objectives: Observationally, homocysteine is positively associated with ischemic heart disease (IHD) and unhealthy lipids; folate and vitamin B12, which reduce homocysteine, are associated with lower IHD risk and healthy lipids. Randomized controlled trials have shown no benefits of folate and vitamin B12 for IHD. To clarify the role of these potential targets of intervention in IHD we assessed how genetically determined homocysteine, folate and vitamin-B12-affected IHD and lipids.

Subjects/methods: Separate-sample instrumental variable analysis with genetic instruments, that is, Mendelian randomization, was used to obtain unconfounded estimates (based on strongly related single-nucleotide polymorphisms (SNPs)) using CARDIoGRAMplusC4D, a large coronary artery disease/myocardial infarction (CAD/MI) case (n=64 374)-control (n=130 681) study with extensive genotyping, and the Global Lipids Genetics Consortium Results (n=196 475).

Results: Homocysteine was unrelated to CAD/MI (odds ratio (OR) 1.07 per log-transformed s.d., 95% confidence interval (CI) 0.96 to 1.19) based on 14 SNPs, as was folate (OR 1.18 per s.d., 95% CI 0.80 to 1.75) based on rs153734, and vitamin B12 (OR 0.98 per log-transformed s.d., 95% CI 0.85 to 1.14) based on rs602662, rs9473555, rs526934 and rs11254363. Homocysteine and folate were not clearly associated with lipids, vitamin B12 was associated with higher inverse normal transformed low-density lipoprotein cholesterol (0.07, 95% CI 0.02 to 0.12) and triglycerides (0.05, 95% CI 0.004 to 0.09).

Conclusions: Our findings do not corroborate the observed positive association of homocysteine or negative associations of folate and vitamin B12 with CAD/MI. Vitamin B12 might be associated with an unfavorable lipid profile.

Citing Articles

How Do Minerals, Vitamins, and Intestinal Microbiota Affect the Development and Progression of Heart Disease in Adult and Pediatric Patients?.

Brecht P, Dring J, Yanez F, Styczen A, Mertowska P, Mertowski S Nutrients. 2023; 15(14).

PMID: 37513682 PMC: 10384570. DOI: 10.3390/nu15143264.

Homocysteine induces ferroptosis in endothelial cells through the systemXc/GPX4 signaling pathway.

Shi J, Chen D, Wang Z, Li S, Zhang S BMC Cardiovasc Disord. 2023; 23(1):316.

PMID: 37355559 PMC: 10290364. DOI: 10.1186/s12872-023-03342-4.

Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank.

Wang L, Li X, Montazeri A, MacFarlane A, Momoli F, Duthie S Am J Clin Nutr. 2023; 117(3):564-575.

PMID: 36811473 PMC: 7614280. DOI: 10.1016/j.ajcnut.2023.01.005.

Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study.

Yuan S, Mason A, Carter P, Burgess S, Larsson S BMC Med. 2021; 19(1):97.

PMID: 33888102 PMC: 8063383. DOI: 10.1186/s12916-021-01977-8.

Effects of selenium on coronary artery disease, type 2 diabetes and their risk factors: a Mendelian randomization study.

Rath A, Lam H, Schooling C Eur J Clin Nutr. 2021; 75(11):1668-1678.

PMID: 33828238 DOI: 10.1038/s41430-021-00882-w.

References

Graham I . Homocysteine in health and disease. Ann Intern Med. 1999; 131(5):387-8. DOI: 10.7326/0003-4819-131-5-199909070-00010. View

Refsum H, Nurk E, Smith A, Ueland P, Gjesdal C, Bjelland I . The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006; 136(6 Suppl):1731S-1740S. DOI: 10.1093/jn/136.6.1731S. View

Toole J, Malinow M, Chambless L, Spence J, Pettigrew L, Howard V . 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(5):565-75. DOI: 10.1001/jama.291.5.565. View

Hazra A, Kraft P, Lazarus R, Chen C, Chanock S, Jacques P . Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Hum Mol Genet. 2009; 18(23):4677-87. PMC: 2773275. DOI: 10.1093/hmg/ddp428. View

Willer C, Schmidt E, Sengupta S, Peloso G, Gustafsson S, Kanoni S . Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45(11):1274-1283. PMC: 3838666. DOI: 10.1038/ng.2797. View

Rafnsson S, Saravanan P, Bhopal R, Yajnik C . Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor? A systematic review of cohort studies. Eur J Nutr. 2010; 50(2):97-106. DOI: 10.1007/s00394-010-0119-6. View

Kalin M, Zumoff B . Sex hormones and coronary disease: a review of the clinical studies. Steroids. 1990; 55(8):330-52. DOI: 10.1016/0039-128x(90)90058-j. View

Collin S, Metcalfe C, Palmer T, Refsum H, Lewis S, Davey Smith G . The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers?. Int J Mol Epidemiol Genet. 2011; 2(4):316-27. PMC: 3243448. View

Nikpay M, Goel A, Won H, Hall L, Willenborg C, Kanoni S . A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015; 47(10):1121-1130. PMC: 4589895. DOI: 10.1038/ng.3396. View

10.

Schunkert H, Konig I, Kathiresan S, Reilly M, Assimes T, Holm H . Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet. 2011; 43(4):333-8. PMC: 3119261. DOI: 10.1038/ng.784. View

11.

Olthof M, van Vliet T, Verhoef P, Zock P, Katan M . Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans. PLoS Med. 2005; 2(5):e135. PMC: 1140947. DOI: 10.1371/journal.pmed.0020135. View

12.

Choi J, Yates Z, Veysey M, Heo Y, Lucock M . Contemporary issues surrounding folic Acid fortification initiatives. Prev Nutr Food Sci. 2015; 19(4):247-60. PMC: 4287316. DOI: 10.3746/pnf.2014.19.4.247. View

13.

. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002; 288(16):2015-22. DOI: 10.1001/jama.288.16.2015. View

14.

Marti-Carvajal A, Sola I, Lathyris D, Salanti G . Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2009; (4):CD006612. PMC: 4164174. DOI: 10.1002/14651858.CD006612.pub2. View

15.

Carmel R . Mandatory fortification of the food supply with cobalamin: an idea whose time has not yet come. J Inherit Metab Dis. 2010; 34(1):67-73. PMC: 3026896. DOI: 10.1007/s10545-010-9150-2. View

16.

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. 2014; 54(3):455-64. DOI: 10.1007/s00394-014-0729-5. View

17.

Armitage J, Bowman L, Clarke R, Wallendszus K, Bulbulia R, Rahimi K . 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(24):2486-94. DOI: 10.1001/jama.2010.840. View

18.

Badri S, Vanithakumari G, Malini T . Studies on methotrexate effects on testicular steroidogenesis in rats. Endocr Res. 2000; 26(2):247-62. DOI: 10.3109/07435800009066165. View

19.

Everett B, Pradhan A, Solomon D, Paynter N, MacFadyen J, Zaharris E . Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013; 166(2):199-207.e15. PMC: 3888829. DOI: 10.1016/j.ahj.2013.03.018. View

20.

Tchetgen Tchetgen E, Walter S, Glymour M . Commentary: building an evidence base for mendelian randomization studies: assessing the validity and strength of proposed genetic instrumental variables. Int J Epidemiol. 2013; 42(1):328-31. PMC: 3600630. DOI: 10.1093/ije/dyt023. View