Skip to main content Accessibility help

Effect of long-term low-dose folic acid supplementation on degree of total homocysteine-lowering: major effect modifiers

  • Binyan Wang (a1) (a2), Hongxu Wu (a1), Youbao Li (a2), Qianyun Ban (a1), Xiao Huang (a3), Lulu Chen (a1), Jianping Li (a4), Yan Zhang (a4), Yimin Cui (a5), Mingli He (a6), Genfu Tang (a1), Delu Yin (a7), Junnong Li (a8), Yong Huo (a3), Xianhui Qin (a1) (a2) and Xiping Xu (a1) (a2)...


We sought to examine the potential modifiers in the association between long-term low-dose folic acid supplementation and the reduction of serum total homocysteine (tHcy) among hypertensive patients, using data from the China Stroke Primary Prevention Trial (CSPPT). This analysis included 16 867 participants who had complete data on tHcy measurements at both the baseline and exit visit. After a median treatment period of 4·5 years, folic acid treatment significantly reduced the tHcy levels by 1·6 μmol/l (95 % CI 1·4, 1·8). More importantly, after adjustment for baseline tHcy and other important covariates, a greater degree of tHcy reduction was observed in certain subgroups: males, the methylenetetrahydrofolate reductase (MTHFR) 677TT genotype, higher baseline tHcy levels (≥12·5 (median) v. <12·5 μmol/l), lower folate levels (<8·0 (median) v. ≥8·0 ng/ml), estimated glomerular filtration rate (eGFR) <60 ml/min per 1·73 m2 (v. 60–<90 and ≥90 ml/min per 1·73 m2), ever smokers and concomitant use of diuretics (P for all interactions <0·05). The degree of tHcy reduction associated with long-term folic acid supplementation can be significantly affected by sex, MTHFR C677T genotypes, baseline folate, tHcy, eGFR levels and smoking status.


Corresponding author

*Corresponding authors: X. Qin, fax +86 551 5161211, email; X. Xu, fax +86 551 5161211, email


Hide All
1. Wald, DS, Law, M & Morris, JK (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325, 1202.
2. Stanger, O, Herrmann, W, Pietrzik, K, et al. (2003) DACH-LIGA homocystein (German, Austrian and Swiss Homocysteine Society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations. Clin Chem Lab Med 41, 13921403.
3. Xie, D, Yuan, Y, Guo, J, et al. (2015) Hyperhomocysteinemia predicts renal function decline: a prospective study in hypertensive adults. Sci Rep 5, 16268.
4. Towfighi, A, Markovic, D & Ovbiagele, B (2010) Pronounced association of elevated serum homocysteine with stroke in subgroups of individuals: a nationwide study. J Neurol Sci 298, 153157.
5. Li, J, Jiang, S, Zhang, Y, et al. (2015) H-type hypertension and risk of stroke in Chinese adults: a prospective, nested case–control study. J Transl Int Med 3, 171178.
6. Qin, X, Li, Y, Sun, N, et al. (2017) Elevated homocysteine concentrations decrease the antihypertensive effect of angiotensin-converting enzyme inhibitors in hypertensive patients. Arterioscler Thromb Vasc Biol 37, 166172.
7. Li, Y, Huang, T, Zheng, Y, et al. (2016) Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. J Am Heart Assoc 5, e003768.
8. Qin, X, Xu, M, Zhang, Y, et al. (2012) Effect of folic acid supplementation on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis 222, 307313.
9. Huang, X, Li, Y, Li, P, et al. (2017) Association between percent decline in serum total homocysteine and risk of first stroke. Neurology 89, 21012107.
10. Huo, Y, Qin, X, Wang, J, et al. (2012) Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. Int J Clin Pract 66, 544551.
11. Yang, HT, Lee, M, Hong, KS, et al. (2012) Efficacy of folic acid supplementation in cardiovascular disease prevention: an updated meta-analysis of randomized controlled trials. Eur J Intern Med 23, 745754.
12. Zhao, M, Wu, G, Li, Y, et al. (2017) Meta-analysis of folic acid efficacy trials in stroke prevention: insight into effect modifiers. Neurology 88, 18301838.
13. Homocysteine Lowering Trialists’ Collaboration (2005) Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 82, 806812.
14. Huo, Y, Li, J, Qin, X, et al. (2015) Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA 313, 13251335.
15. Xu, X, Qin, X, Li, Y, et al. (2016) Efficacy of folic acid therapy on the progression of chronic kidney disease: the renal substudy of the China Stroke Primary Prevention Trial. JAMA Intern Med 176, 14431450.
16. Robertson, J, Iemolo, F, Stabler, SP, et al. (2005) Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products. CMAJ 172, 15691573.
17. Refsum, H, Smith, AD, Ueland, PM, et al. (2004) Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 50, 332.
18. Mathews, F, Yudkin, P, Smith, RF, et al. (2000) Nutrient intakes during pregnancy: the influence of smoking status and age. J Epidemiol Community Health 54, 1723.
19. Ortega, RM, Requejo, AM, Lopez-Sobaler, AM, et al. (2004) Smoking and passive smoking as conditioners of folate status in young women. J Am Coll Nutr 23, 365371.
20. Yanbaeva, DG, Dentener, MA, Creutzberg, EC, et al. (2007) Systemic effects of smoking. Chest 131, 15571566.
21. Ulvik, A, Ebbing, M, Hustad, S, et al. (2010) Long- and short-term effects of tobacco smoking on circulating concentrations of B vitamins. Clin Chem 56, 755763.
22. Homocysteine Lowering Trialists’ Collaboration (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 316, 894898.
23. Qin, X, Li, J, Cui, Y, et al. (2012) MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults. Nutr J 11, 2.
24. Ho, GY, Eikelboom, JW, Hankey, GJ, et al. (2006) Methylenetetrahydrofolate reductase polymorphisms and homocysteine-lowering effect of vitamin therapy in Singaporean stroke patients. Stroke 37, 456460.
25. Fohr, IP, Prinz-Langenohl, R, Bronstrup, A, et al. (2002) 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr 75, 275282.
26. Quinlivan, EP, McPartlin, J, McNulty, H, et al. (2002) Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 359, 227228.
27. Spence, JD, Yi, Q & Hankey, GJ (2017) B vitamins in stroke prevention: time to reconsider. Lancet Neurol 16, 750760.
28. Spence, JD, Urquhart, BL & Bang, H (2016) Effect of renal impairment on atherosclerosis: only partially mediated by homocysteine. Nephrol Dial Transplant 31, 937944.
29. Qin, X, Zhang, Y, Cai, Y, et al. (2013) Prevalence of obesity, abdominal obesity and associated factors in hypertensive adults aged 45–75 years. Clin Nutr 32, 361367.
30. Qin, X, Li, J, Spence, JD, et al. (2016) Folic acid therapy reduces the first stroke risk associated with hypercholesterolemia among hypertensive patients. Stroke 47, 28052812.
31. Verhaar, MC, Stroes, E & Rabelink, TJ (2002) Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol 22, 613.
32. Albert, CM, Cook, NR, Gaziano, JM, et al. (2008) 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 299, 20272036.
33. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage, JM, Bowman, L, et al. (2010) 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 303, 24862494.
34. Bostom, AG, Carpenter, MA, Kusek, JW, et al. (2011) Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation trial. Circulation 123, 17631770.


Type Description Title
Supplementary materials

Wang et al. supplementary material
Tables S1-S6 and Figure S1

 PDF (348 KB)
348 KB


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed