Novel micronutrient associations in homocysteine metabolism

Main Article Content

Hari K Krishnamurthy https://orcid.org/0000-0002-7832-8423
Swarnkumar Reddy
Vasanth Jayaraman
Karthik Krishna
Qi Song
Tianhao Wang
Kang Bei
John J Rajasekaran

Keywords

Homocysteine, Micronutrients, Methionine, Vitamins, Amino acids, cardiovascular diseases

Abstract

Abstract


Objective: Elevated serum levels of homocysteine are one of the most effective biomarkers in diagnosing atherosclerotic cardiovascular disease and associated disorders. The elevated levels of homocysteine may result from mutations in genes coding vital enzymes or other environmental factors such as nutrition, medications, increased methionine intake, pregnancy, etc.


Methods: The association of 36 vital micronutrients with circulating levels of homocysteine in a population of 336 free-living individuals was analyzed. Baseline serum homocysteine concentration was measured by enzyme-linked immunosorbent assay using Beckman Counter AU series Analyzers.  


Results: Non-parametric analysis by Mann-Whitney U test as well as Pearson’s correlation showed a strong association of vitamin B9 (folate) and vitamin B12 with high serum levels of homocysteine. Interestingly several amino acids including asparagine, isoleucine, cysteine, citrulline, and carnitine exhibited a positive correlation with serum homocysteine. Among vitamins and minerals, vitamin A and selenium were positively correlated with circulating homocysteine.


Conclusion: The study suggests that the serum levels of several micronutrients act as confounding variables in regulating the circulating levels of homocysteine. Several novel nutrient associations for modulating levels of homocysteine are highlighted.  Given that homocysteine is a modifiable risk factor, these nutrients could play an important role in preventive care settings and should be further investigated clinically.

Abstract 325 | PDF Downloads 333

References

1. Kreatsoulas, C. and Anand, S.S. The impact of social determinants on cardiovascular disease. Can J Cardiol 2010; 26: 8C-13C.
2. Rahman, K. and Lowe, G.M. Garlic and cardiovascular disease: a critical review. J Nutr 2006; 136(3); 736S-740S.
3. Krishnamurthy, H.K., Reddy, S., Jayaraman, V., Krishna, K., Song, Q., Rajasekaran, K.E., Wang, T., Bei, K. and Rajasekaran, J.J. Effect of Micronutrients on Thyroid Parameters. J. Thyroid Res 2021.
4. Freeman, D.J., Norrie, J., Caslake, M.J., Gaw, A., Ford, I., Lowe, G.D., O’Reilly, D.S.J., Packard, C.J., Sattar, N. and West of Scotland Coronary Prevention Study Group. C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 2002; 51(5): 1596-1600.
5. Kaul, S., Zadeh, A.A. and Shah, P.K. Homocysteine hypothesis for atherothrombotic cardiovascular disease: not validated. J. Am. Coll. Cardiol 2006; 48(5): 914-923.
6. Streck, E.L., Vieira, P.S., Wannmacher, C., Dutra-Filho, C.S., Wajner, M. and Wyse, A.T. In vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampus. Metab. Brain Dis 200; 18(2): 147-154.
7. McCully, K.S. Homocysteine and vascular disease. Nat. Med 1996; 2(4): 386-389.
8. Zhou, J., Møller, J., Danielsen, C.C., Bentzon, J., Ravn, H.B., Austin, R.C. and Falk, E. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21(9): 1470-1476.
9. Obeid, R. and Herrmann, W. Homocysteine and lipids: S-adenosyl methionine as a key intermediate. FEBS letters 2009; 583(8): 1215-1225.
10. ALI, A.K. Establishing a relationship between serum homocysteine levels and disease severity in adults with sickle cell anaemia in Lagos university teaching hospital (LUTH) 2015; Lagos, Nigeria. Faculty of Pathology.
11. Langman, L.J. and Cole, D.E. Homocysteine. Crit. Rev. Clin. Lab. Sci 1999; 36(4): 365-406.
12. Herrmann, W., Schorr, H., Purschwitz, K., Rassoul, F. and Richter, V. Total homocysteine, vitamin B12, and total antioxidant status in vegetarians. Clin chem 2001; 47(6): 1094-1101.
13. Fenech MF, Dreosti IE, Rinaldi JR. Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis. 1997; 18(7): 1329-36.
14. Cagnacci, A., Baldassari, F., Rivolta, G., Arangino, S. and Volpe, A. Relation of homocysteine, folate, and vitamin B12 to bone mineral density of postmenopausal women. Bone 2003; 33(6): 956-959.
15. Thiamin, R. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. 1998; 6015.
16. Satyanarayana, A., Balakrishna, N., Pitla, S., Reddy, P.Y., Mudili, S., Lopamudra, P., Suryanarayana, P., Viswanath, K., Ayyagari, R. and Reddy, G.B. Status of B-vitamins and homocysteine in diabetic retinopathy: association with vitamin-B12 deficiency and hyperhomocysteinemia. PloS one 2011; 6(11): 26747.
17. Rush, E.C., Katre, P. and Yajnik, C.S. Vitamin B12: one carbon metabolism, fetal growth and programming for chronic disease. Eur. J. Clin. Nutr 2014; 68(1): 2-7.
18. Aggrey, S.E., González‐Cerón, F., Rekaya, R. and Mercier, Y. Gene expression differences in the methionine remethylation and transsulphuration pathways under methionine restriction and recovery with D, L‐methionine or D, L‐HMTBA in meat‐type chickens. J Anim Physiol Anim Nutr 2018; 102(1): 468-e475.
19. Fenech, M. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat. Res. - Fundam. Mol. Mech. Mutagen 2012; 733(1-2): 21-33.
20. Ingenbleek, Y. The oxidative stress of hyperhomocysteinemia results from reduced bioavailability of sulfur-containing reductants. Clin. Chem 2011; 4(1).
21. Vazquez-Lorente, H., Herrera-Quintana, L., Molina-López, J., Gamarra, Y. and Planells, E. Effect of zinc supplementation on circulating concentrations of homocysteine, vitamin B12, and folate in a postmenopausal population. J. Trace Elem. Med. Biol 2022; 71: 126942.
22. Ostrakhovitch, E.A. and Tabibzadeh, S. Homocysteine and age-associated disorders. Ageing Res. Rev 2019; 49: 144-164.
23. Mattson, M.P., Kruman, I.I. and Duan, W. Folic acid and homocysteine in age-related disease. Ageing Res. Rev 2002; 1(1): 95-111.
24. Raslova, K., Bederova, A., Gašparovič, J. and Blažíček, P. Effect of Diet and 677 C–» T 5, 10-Methylenetetrahydrofolate Reductase Genotypes on Plasma Homocyst(e)ine. Physiol. Res 2000; 49: 651-658.
25. Skovierova, H., Vidomanova, E., Mahmood, S., Sopkoa, J., Drgova, A., Cervenova, T., Halasova, E. and Lehotsky, J. The molecular and cellular effect of homocysteine metabolism imbalance on human health. International journal of molecular sciences 2016; 17(10):1733.
26. Kataria, N., Yadav, P., Kumar, R., Kumar, N., Singh, M., Kant, R. and Kalyani, V. Effect of vitamin B6, B9, and B12 supplementation on homocysteine level and cardiovascular outcomes in stroke patients: a meta-analysis of randomized controlled trials. Cureus 2021; 13(5).
27. Lyon, P., Strippoli, V., Fang, B. and Cimmino, L. B vitamins and one-carbon metabolism: implications in human health and disease. Nutrients 2020; 12(9): 2867.
28. Ganji, Vijay, and Mohammad R. Kafai. Frequent consumption of milk, yogurt, cold breakfast cereals, peppers, and cruciferous vegetables and intakes of dietary folate and riboflavin but not vitamins B-12 and B-6 are inversely associated with serum total homocysteine concentrations in the US population. Am. J. Clin. Nutr 2004; 80: 1500-1507.
29. Olsen, T., Vinknes, K.J., Svingen, G.F., Pedersen, E.R., Dhar, I., Tell, G.S., Blomhoff, R., Ueland, P.M., Midttun, Ø., Refsum, H. and Nygård, O.K. The risk association of plasma total homocysteine with acute myocardial infarction is modified by serum vitamin A. Eur. J. Prev. Cardiol 2008; 25(15): 1612-1620.
30. Puddu, P.E. Serum vitamin A, total homocysteine and acute myocardial infarction: is there a causal association? Eur. J. Prev. Cardiol 2018; 25(15): 1607-1611.
31. González, S., Huerta, J.M., Fernández, S., Patterson, A.M. and Lasheras, C. Homocysteine increases the risk of mortality in elderly individuals. Br. J. Nutr 2007; 97(6): 1138-1143.
32. Gonzalez, S., Huerta, J.M., Álvarez-Uría, J., Fernandez, S., Patterson, A.M. and Lasheras, C. Serum selenium is associated with plasma homocysteine concentrations in elderly humans. J Nutr 2004; 134(7): 1736-1740.
33. Stranges, S., Laclaustra, M., Ji, C., Cappuccio, F.P., Navas-Acien, A., Ordovas, J.M., Rayman, M. and Guallar, E. Higher selenium status is associated with adverse blood lipid profile in British adults. J Nutr 2010; 140(1): 81-87.
34. Myles, P.S., Chan, M.T., Kaye, D.M., McIlroy, D.R., Lau, C.W., Symons, J.A. and Chen, S. Effect of nitrous oxide anesthesia on plasma homocysteine and endothelial function. The Journal of the American Society of Anesthesiologists 2008; 109(4): 657-663.
35. Jin, L., Caldwell, R.B., Li-Masters, T. and Caldwell, R.W. Homocysteine induces endothelial dysfunction via inhibition of arginine transport. J. Physiol. Pharmacol 2007; 58(2): 191.
36. Ntzouvani, A., Nomikos, T., Panagiotakos, D., Fragopoulou, E., Pitsavos, C., McCann, A., Ueland, P.M. and Antonopoulou, S. Amino acid profile and metabolic syndrome in a male Mediterranean population: a cross-sectional study. Nutr Metab Cardiovasc Dis 2017; 27(11): 1021-1030.
37. Kokot, F., Chudek, J., Łysiak-SzydŁowska, W., Domagała, B., Adamczak, M., Ignacy, W., Kania, M., Rutkowski, B., Szczeklik, A. and Wiecek, A. Levels of carnitine and homocysteine in plasma of long-term hemodialysis patients with chronic renal failure. Polskie Arch. Med. Wewnetrznej 2001; 106(6): 1131-1136.