{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:17:21Z","timestamp":1790777841126,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2500503"],"award-info":[{"award-number":["2021YFC2500503"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of 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Peptides","award":["81703288"],"award-info":[{"award-number":["81703288"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The relationship between folate concentrations and stroke risk remains unestablished, and the mediation effect of homocysteine (Hcy) and interaction effect of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has yet to be investigated. This cohort study involved 4903 subjects derived from a Chinese community population. The association between folate and first stroke was examined in Cox proportional hazard regression models. The mediation analyses involving Hcy and the undiscovered modification of the MTHFR C677T genotype were assessed. The mean (SD) age of subjects was 56.7 (8.8) years old, and 37.0% were male. A total of 407 strokes, 375 ischemic strokes and 47 hemorrhagic strokes occurred during the mean (SD) follow-up of 9.3 (1.8) years. The participants in the highest folate quartile (\u22658.2 ng\/mL) exhibited a lower stroke risk compared to those in the lowest quartile (hazard ratio [HR]: 0.68, 95% confidence interval [CI]: 0.50\u20130.93, p = 0.017; p for trend = 0.009). Hcy significantly mediated 14.51% of the relationship between folate and stroke in the fully adjusted model. Only in individuals with the MTHFR 677CC genotype but not CT\/TT genotype was folate adversely correlated with stroke (HR: 0.88, 95% CI: 0.79\u20130.97, p for interaction = 0.026) and ischemic stroke (HR: 0.88, 95% CI: 0.80\u20130.98, p for interaction = 0.035). Insufficient folate concentrations were associated with a heightened 10-year stroke risk, in which Hcy concentrations played a crucial mediating role. MTHFR C677T gene polymorphism could potentially modify the folate\u2013stroke relationship.<\/jats:p>","DOI":"10.3390\/nu17010159","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T12:37:19Z","timestamp":1735648639000},"page":"159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Association Between Serum Folate Concentrations and 10-Year Stroke Risk in a Prospective Community Cohort: Mediation and Interaction Analyses"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9311-4431","authenticated-orcid":false,"given":"Zhe","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8351-4821","authenticated-orcid":false,"given":"Fangfang","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3676-4999","authenticated-orcid":false,"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8526-1095","authenticated-orcid":false,"given":"Jianping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7508-4160","authenticated-orcid":false,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"},{"name":"Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"ref_1","first-page":"10258","article-title":"Folate\u2014A scoping review for Nordic Nutrition Recommendations 2023","volume":"67","author":"Ueland","year":"2023","journal-title":"Food Nutr. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dang, S., Jain, A., Dhanda, G., Bhattacharya, N., Bhattacharya, A., and Senapati, S. (2024). One carbon metabolism and its implication in health and immune functions. Cell Biochem. Funct., 42.","DOI":"10.1002\/cbf.3926"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1038\/s41440-023-01249-3","article-title":"Non-linear associations of serum and red blood cell folate with risk of cardiovascular and all-cause mortality in hypertensive adults","volume":"46","author":"Xu","year":"2023","journal-title":"Hypertens. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.tjnut.2023.01.023","article-title":"Associations of Serum Folate and Homocysteine Concentrations with All-Cause, Cardiovascular Disease, and Cancer Mortality in Men and Women in Korea: The Cardiovascular Disease Association Study","volume":"153","author":"Song","year":"2023","journal-title":"J. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e2146124","DOI":"10.1001\/jamanetworkopen.2021.46124","article-title":"Associations of Serum Folate and Vitamin B12 Levels with Cardiovascular Disease Mortality Among Patients with Type 2 Diabetes","volume":"5","author":"Liu","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sun, Y., Zhang, H., Qi, G., and Tian, W. (2024). Nutrient deficiency patterns and all-cause and cardiovascular mortality in older adults with hypertension: A latent class analysis. BMC Public Health, 24.","DOI":"10.1186\/s12889-024-19003-w"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1093\/eurjpc\/zwae022","article-title":"Homocysteine, hyperhomocysteinemia, and H-type hypertension","volume":"31","author":"Wu","year":"2024","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e364","DOI":"10.1161\/STR.0000000000000375","article-title":"2021 Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack: A Guideline from the American Heart Association\/American Stroke Association","volume":"52","author":"Kleindorfer","year":"2021","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1016\/j.jacc.2022.09.048","article-title":"Micronutrient Supplementation to Reduce Cardiovascular Risk","volume":"80","author":"An","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1161\/01.STR.0000169934.96354.3a","article-title":"Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: A prospective, nested case-referent study of plasma concentrations and dietary intake","volume":"36","author":"Hultdin","year":"2005","journal-title":"Stroke"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1161\/STROKEAHA.108.524934","article-title":"Is ischemic stroke risk related to folate status or other nutrients correlated with folate intake?","volume":"39","author":"Weng","year":"2008","journal-title":"Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5462","DOI":"10.1080\/10408398.2021.1885341","article-title":"The role of B vitamins in stroke prevention","volume":"62","author":"Bjorklund","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Raghubeer, S., and Matsha, T.E. (2021). Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks. Nutrients, 13.","DOI":"10.3390\/nu13124562"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41421-023-00582-8","article-title":"The STROMICS genome study: Deep whole-genome sequencing and analysis of 10K Chinese patients with ischemic stroke reveal complex genetic and phenotypic interplay","volume":"9","author":"Cheng","year":"2023","journal-title":"Cell Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1093\/ije\/dyad147","article-title":"MTHFR and risk of stroke and heart disease in a low-folate population: A prospective study of 156,000 Chinese adults","volume":"52","author":"Bennett","year":"2023","journal-title":"Int. J. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhao, L., Li, T., Dang, M., Li, Y., Fan, H., Hao, Q., Song, D., Lu, J., Lu, Z., and Jian, Y. (2022). Association of methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C>T) gene polymorphism with ischemic stroke risk in different populations: An updated meta-analysis. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1021423"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1016\/S0140-6736(07)61602-X","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies","volume":"370","author":"Altman","year":"2007","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJMoa1114248","article-title":"Estimating glomerular filtration rate from serum creatinine and cystatin C","volume":"367","author":"Inker","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Liang, Z., Li, K., Chen, H., Jia, J., Li, J., Huo, Y., Fan, F., and Zhang, Y. (2024). The Association of Plasma Homocysteine Concentrations with a 10-Year Risk of All-Cause and Cardiovascular Mortality in a Community-Based Chinese Population. Nutrients, 16.","DOI":"10.3390\/nu16121945"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1001\/jama.2018.21973","article-title":"Mediation Analysis","volume":"321","author":"Lee","year":"2019","journal-title":"JAMA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1186\/s12967-023-04276-3","article-title":"Association of impaired sensitivity to thyroid hormones with hyperuricemia through obesity in the euthyroid population","volume":"21","author":"Wu","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Burgess, K., Bennett, C., Mosnier, H., Kwatra, N., Bethel, F., and Jadavji, N.M. (2020). The Antioxidant Role of One-Carbon Metabolism on Stroke. Antioxidants, 9.","DOI":"10.3390\/antiox9111141"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1097\/MCO.0000000000000743","article-title":"The role of dietary supplements that modulate one-carbon metabolism on stroke outcome","volume":"24","author":"Yahn","year":"2021","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1001\/jama.2015.2274","article-title":"Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: The CSPPT randomized clinical trial","volume":"313","author":"Huo","year":"2015","journal-title":"JAMA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/01.hjr.0000160834.75466.b0","article-title":"Serum homocysteine, folate and risk of stroke: Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study","volume":"12","author":"Virtanen","year":"2005","journal-title":"Eur. J. Cardiovasc. Prev. Rehabil."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yuan, S., Mason, A.M., Carter, P., Burgess, S., and Larsson, S.C. (2021). Homocysteine, B vitamins, and cardiovascular disease: A Mendelian randomization study. BMC Med., 19.","DOI":"10.1186\/s12916-021-01977-8"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1161\/STROKEAHA.107.486068","article-title":"B vitamin plasma levels and the risk of ischemic stroke and transient ischemic attack in a German cohort","volume":"38","author":"Weikert","year":"2007","journal-title":"Stroke"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.ajcnut.2023.01.005","article-title":"Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: Analysis of the UK Biobank","volume":"117","author":"Wang","year":"2023","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e16444","DOI":"10.1016\/j.heliyon.2023.e16444","article-title":"Homocysteine levels, H-Hypertension, and the MTHFR C677T genotypes: A complex interaction","volume":"9","author":"Alefishat","year":"2023","journal-title":"Heliyon"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/s41392-023-01313-x","article-title":"B cell-derived anti-beta 2 glycoprotein I antibody mediates hyperhomocysteinemia-aggravated hypertensive glomerular lesions by triggering ferroptosis","volume":"8","author":"Du","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1182\/bloodadvances.2021004572","article-title":"The binding of autotaxin to integrins mediates hyperhomocysteinemia-potentiated platelet activation and thrombosis in mice and humans","volume":"6","author":"Han","year":"2022","journal-title":"Blood Adv."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Shi, W., Zhang, J., Zhao, W., Yue, M., Ma, J., Zeng, S., Tang, J., Wang, Y., and Zhou, Z. (2024). Intracellular Iron Deficiency and Abnormal Metabolism, Not Ferroptosis, Contributes to Homocysteine-Induced Vascular Endothelial Cell Death. Biomedicines, 12.","DOI":"10.3390\/biomedicines12102301"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e1126","DOI":"10.1212\/WNL.0000000000008932","article-title":"Interaction of serum vitamin B(12) and folate with MTHFR genotypes on risk of ischemic stroke","volume":"94","author":"Qin","year":"2020","journal-title":"Neurology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"128","DOI":"10.2478\/jtim-2023-0087","article-title":"The evolution of folate supplementation\u2014From one size for all to personalized, precision, poly-paths","volume":"11","author":"He","year":"2023","journal-title":"J. Transl. Int. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/1\/159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:58:14Z","timestamp":1760115494000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/1\/159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,31]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["nu17010159"],"URL":"https:\/\/doi.org\/10.3390\/nu17010159","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,31]]}}}