{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:20:45Z","timestamp":1788276045548,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Evidence Based Medicine"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Several studies suggested that the risk of cardiovascular disease (CVD) had increased before individuals developed hyperhomocysteinemia. This study aimed to investigate the dose\u2013response relationship between circulating homocysteine (Hcy) levels and the risk of CVD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Observational studies examining the relationship between circulating Hcy levels and CVD risks were included. Searches were conducted on English databases (PubMed, Embase, and Web of Science) and Chinese databases (CNKI, WanFang, VIP, and SinoMed) in May 2025. Combined relative risks (RRs) or odds ratios (ORs) were calculated using random\u2010effects models. The dose\u2013response relationship between circulating Hcy levels and CVD risks was assessed using restricted cubic spline analysis. The risk of bias was assessed using the Newcastle\u2013Ottawa Scale for cohort and case\u2010control studies, and the Agency for Healthcare Research and Quality criteria for cross\u2010sectional studies. Publication bias was assessed using funnel plots and the trim\u2010and\u2010fill method.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 117 original studies (35 cohort studies, 60 case\u2010control studies, and 22 cross\u2010sectional studies) were included, involving 504,469 participants with 43,089 CVD cases. Elevated circulating Hcy levels were significantly associated with increased CVD risks in all study types (RRs\/ORs: 1.61\u20132.14). A non\u2010linear dose\u2013response relationship was observed between circulating Hcy levels and CVD risks (all\n                      <jats:italic>p<\/jats:italic>\n                      &lt; 0.001), with thresholds at 10.4 \u00b5mol\/L for cohort studies, and 10.0 \u00b5mol\/L for both case\u2010control studies and cross\u2010sectional studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this meta\u2010analysis, increased Hcy levels were linked to higher CVD risks. Circulating Hcy level &gt;10 \u00b5mol\/L may implement nutritional intervention in primary prevention of CVD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jebm.70080","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T04:30:03Z","timestamp":1759293003000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Intervention at Circulating Homocysteine Levels &gt;10 \u00b5mol\/L for Primary Prevention of Cardiovascular Diseases: A Systematic Review and Dose\u2013Response Meta\u2010Analysis"],"prefix":"10.1111","volume":"18","author":[{"given":"Zihui","family":"Huang","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiupeng","family":"Zou","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengchu","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruikun","family":"He","sequence":"additional","affiliation":[{"name":"Research and Development Center BYHEALTH Institute of Nutrition &amp; Health Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zeng","sequence":"additional","affiliation":[{"name":"Nutrition Department Guangzhou Shiyuan Health Management Company Limited Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijun","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huabin","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Lu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"},{"name":"Department of Clinical Nutrition Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5019-2827","authenticated-orcid":false,"given":"Huilian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"issue":"12","key":"e_1_2_7_2_1","first-page":"743","article-title":"Effect of Advanced Age on Plasma Homocysteine Levels and Its Association With Ischemic Stroke in Non\u2010Valvular Atrial Fibrillation","volume":"14","author":"Yao Y.","year":"2017","journal-title":"Journal of Geriatric Cardiology"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcn112"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2011.062"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1123\/ijsnem.16.4.341"},{"issue":"1","key":"e_1_2_7_6_1","first-page":"97","article-title":"Homocysteine, B Vitamins, and Cardiovascular Disease: A Mendelian Randomization Study","volume":"19","author":"Yuan S.","year":"2021","journal-title":"BMC Medicine [Electronic Resource]"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.013311"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.1.178"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.288.16.2015"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000026875"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-nutr-071715-050947"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2020.110832"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-019-0216-4"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.4103\/0366-6999.211895"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2891-14-6"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.116.015324"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.288.8.973"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)07391-2"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-08-1077"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.289.10.1251"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.4065\/83.11.1203"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000199147.30016.74"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.100768"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2019.08.019"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2022.03.010"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-199305000-00005"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.numecd.2020.07.026"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001177"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1177\/2047487319894679"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/10641963.2016.1226888"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.05.028"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/jch.13398"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13279"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20040867"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-011-9297-y"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-017-0478-0"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00540.2011"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2005.08.039"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12986-017-0233-z"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041690"}],"container-title":["Journal of Evidence-Based Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jebm.70080","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jebm.70080","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jebm.70080","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T11:41:20Z","timestamp":1769946080000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jebm.70080"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":40,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1111\/jebm.70080"],"URL":"https:\/\/doi.org\/10.1111\/jebm.70080","archive":["Portico"],"relation":{},"ISSN":["1756-5383","1756-5391"],"issn-type":[{"value":"1756-5383","type":"print"},{"value":"1756-5391","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]},"assertion":[{"value":"2025-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70080"}}