{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T10:16:37Z","timestamp":1787739397908,"version":"build-2784847793"},"reference-count":23,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,21]],"date-time":"2024-05-21T00:00:00Z","timestamp":1716249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"S.Lab (SOLOWAYS)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Exploring the link between genetic polymorphisms in folate metabolism genes (MTHFR, MTR, and MTRR) and cardiovascular disease (CVD), this study evaluates the effect of B vitamin supplements (methylfolate, pyridoxal-5\u2032-phosphate, and methylcobalamin) on homocysteine and lipid levels, potentially guiding personalized CVD risk management. In a randomized, double-blind, placebo-controlled trial, 54 patients aged 40\u201375 with elevated homocysteine and moderate LDL-C levels were divided based on MTHFR, MTR, and MTRR genetic polymorphisms. Over six months, they received either a combination of methylfolate, P5P, and methylcobalamin, or a placebo. At the 6 months follow-up, the treatment group demonstrated a significant reduction in homocysteine levels by 30.0% (95% CI: \u221239.7% to \u221220.3%) and LDL-C by 7.5% (95% CI: \u221210.3% to \u22124.7%), compared to the placebo (p &lt; 0.01 for all). In the subgroup analysis, Homozygous Minor Allele Carriers showed a more significant reduction in homocysteine levels (48.3%, 95% CI: \u221262.3% to \u221234.3%, p &lt; 0.01) compared to mixed allele carriers (18.6%, 95% CI: \u221225.6% to \u221211.6%, p &lt; 0.01), with a notable intergroup difference (29.7%, 95% CI: \u221250.7% to \u22128.7%, p &lt; 0.01). LDL-C levels decreased by 11.8% in homozygous carriers (95% CI: \u221215.8% to \u22127.8%, p &lt; 0.01) and 4.8% in mixed allele carriers (95% CI: \u22126.8% to \u22122.8%, p &lt; 0.01), with a significant between-group difference (7.0%, 95% CI: \u221213.0% to \u22121.0%, p &lt; 0.01). Methylfolate, P5P, and methylcobalamin supplementation tailored to genetic profiles effectively reduced homocysteine and LDL-C levels in patients with specific MTHFR, MTR, and MTRR polymorphisms, particularly with homozygous minor allele polymorphisms.<\/jats:p>","DOI":"10.3390\/nu16111550","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T06:54:09Z","timestamp":1716360849000},"page":"1550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Effect of Methylfolate, Pyridoxal-5\u2032-Phosphate, and Methylcobalamin (SolowaysTM) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9494-4234","authenticated-orcid":false,"given":"Evgeny","family":"Pokushalov","sequence":"first","affiliation":[{"name":"Center for New Medical Technologies, 630090 Novosibirsk, Russia"},{"name":"Scientific Research Laboratory, Triangel Scientific, San Francisco, CA 94101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5468-9961","authenticated-orcid":false,"given":"Andrey","family":"Ponomarenko","sequence":"additional","affiliation":[{"name":"Center for New Medical Technologies, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sevda","family":"Bayramova","sequence":"additional","affiliation":[{"name":"Center for New Medical Technologies, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Garcia","sequence":"additional","affiliation":[{"name":"Scientific Research Laboratory, Triangel Scientific, San Francisco, CA 94101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inessa","family":"Pak","sequence":"additional","affiliation":[{"name":"Center for New Medical Technologies, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9675-3044","authenticated-orcid":false,"given":"Evgenya","family":"Shrainer","sequence":"additional","affiliation":[{"name":"Center for New Medical Technologies, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Ermolaeva","sequence":"additional","affiliation":[{"name":"Center for New Medical Technologies, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1878-4467","authenticated-orcid":false,"given":"Dmitry","family":"Kudlay","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Johnson","sequence":"additional","affiliation":[{"name":"Scientific Research Laboratory, Triangel Scientific, San Francisco, CA 94101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Miller","sequence":"additional","affiliation":[{"name":"Scientific Research Laboratory, Triangel Scientific, San Francisco, CA 94101, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.numecd.2019.09.008","article-title":"Worldwide burden of LDL cholesterol: Implications in cardiovascular disease","volume":"30","author":"Mattiuzzi","year":"2020","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/14779072.2018.1497974","article-title":"The current status of homocysteine as a risk factor for cardiovascular disease: A mini review","volume":"16","author":"Chrysant","year":"2018","journal-title":"Expert Rev. Cardiovasc. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1079\/PNS2004390","article-title":"B-vitamins, homocysteine metabolism and CVD","volume":"63","author":"Strain","year":"2004","journal-title":"Proc. Nutr. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6670","DOI":"10.3390\/nu7085303","article-title":"Homocysteine Metabolism Gene Polymorphisms and the Risk of Folate Deficiency","volume":"7","author":"Li","year":"2015","journal-title":"Nutrients"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15548","DOI":"10.1038\/srep15548","article-title":"Role of genetic mutations in folate-related enzyme genes on Male Infertility","volume":"5","author":"Liu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_6","first-page":"326","article-title":"Vitamin supplementation and retinal blood flow in diabetes","volume":"26","author":"Schmidl","year":"2020","journal-title":"Mol. Vis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.biochi.2015.12.020","article-title":"Vitamin B6 and hydrogen sulfide production in the transsulfuration pathway","volume":"126","author":"Gregory","year":"2016","journal-title":"Biochimie"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/jimd.12009","article-title":"Vitamin B12, folate, and the methionine remethylation cycle\u2014Biochemistry, pathways, and regulation","volume":"42","author":"Froese","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pokushalov, E., Ponomarenko, A., Garcia, C., Pak, I., Shrainer, E., Seryakova, M., Johnson, M., and Miller, R. (2024). The Impact of Glu-comannan, Inulin, and Psyllium Supplementation (SolowaysTM) on Weight Loss in Adults with FTO, LEP, LEPR, and MC4R Polymorphisms: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients, 16.","DOI":"10.3390\/nu16040557"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pokushalov, E., Ponomarenko, A., Bayramova, S., Garcia, C., Pak, I., Shrainer, E., Voronina, E., Sokolova, E., Johnson, M., and Miller, R. (2023). Evaluating the Impact of Omega-3 Fatty Acid (SolowaysTM) Supplementation on Lipid Profiles in Adults with PPARG Polymorphisms: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients, 16.","DOI":"10.3390\/nu16010097"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1136\/bmj.325.7374.1202","article-title":"Homocysteine and cardiovascular disease: Causality evidence from a meta-analysis","volume":"325","author":"Wald","year":"2002","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1055\/s-2000-8470","article-title":"Genetic modulation of homocysteinemia","volume":"26","author":"Rozen","year":"2000","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng0595-111","article-title":"A genetic risk factor for vascular disease","volume":"10","author":"Frosst","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0021-9150(02)00204-6","article-title":"Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study","volume":"166","author":"Jacques","year":"2003","journal-title":"Atherosclerosis"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0021-9150(00)00739-5","article-title":"The methionine syn-thase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations","volume":"157","author":"Gaughan","year":"2001","journal-title":"Atherosclerosis"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, J., Liu, G.-C., Dai, X.-L., Wang, J., Jin, M.-H., Mi, N.-N., and Wang, S.-Q. (2020). The N-terminus of MTRR plays a role in MTR reactivation cycle beyond electron transfer. Bioorganic Chem., 100.","DOI":"10.1016\/j.bioorg.2020.103836"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1056\/NEJM199905133401901","article-title":"Impact of folic acid fortification on plasma folate and total homocysteine concentrations","volume":"340","author":"Jacques","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.amepre.2010.11.022","article-title":"The Association Between a Nutritional quality index and risk of chronic disease","volume":"40","author":"Chiuve","year":"2011","journal-title":"Am. J. Prev. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"614S","DOI":"10.1093\/ajcn\/71.2.614s","article-title":"B vitamins, homocysteine, and neurocognitive function in the elderly","volume":"71","author":"Selhub","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1161\/CIRCULATIONAHA.105.580332","article-title":"Riboflavin and homocysteine in MTHFR 677C->T polymorphism","volume":"113","author":"McNulty","year":"2006","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1161\/STROKEAHA.108.529503","article-title":"Homocysteine-lowering therapy and stroke risk, severity, and disability: Additional findings from the HOPE 2 trial","volume":"40","author":"Saposnik","year":"2009","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1056\/NEJMoa060900","article-title":"Homocysteine lowering with folic acid and B vitamins in vascular disease","volume":"354","author":"Lonn","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jacl.2015.02.003","article-title":"National lipid association recommendations for patient-centered management of dyslipidemia","volume":"9","author":"Jacobson","year":"2015","journal-title":"J. Clin. Lipidol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/11\/1550\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:45:55Z","timestamp":1760107555000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/11\/1550"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,21]]},"references-count":23,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["nu16111550"],"URL":"https:\/\/doi.org\/10.3390\/nu16111550","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,21]]}}}