{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:25:35Z","timestamp":1787117135817,"version":"build-2736575974"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Uric acid is considered a potential risk factor for stroke; However, whether the association between hyperuricemia and stroke outcomes follows a linear or nonlinear pattern remains unclear. Therefore, this study conducted a dose\u2013response meta-analysis based on cohort studies to investigate the association between hyperuricemia and stroke outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically searched PubMed, the Cochrane Library, Embase, Web of Science, CNKI, Wanfang, VIP, and the Chinese Biomedical Literature Database from inception to April 2026. Cohort studies reporting the associations of uric acid with stroke incidence and mortality outcomes were included. Dose\u2013response meta-analyses were performed by generalized least-squares estimation and restricted cubic splines with three knots located at the 10th, 50th, and 90th percentiles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 25 cohort studies involving 1,300,263 participants were included. Conventional meta-analysis showed that hyperuricemia was significantly associated with stroke incidence (RR\u202f=\u202f1.20, 95%CI: 1.11\u20131.29) and mortality (RR\u202f=\u202f1.36, 95%CI: 1.17\u20131.58). Subgroup analysis indicated that hyperuricemia significantly increased the risks of stroke incidence (RR\u202f=\u202f1.22, 95%CI: 1.08\u20131.38) and mortality (RR\u202f=\u202f1.42, 95%CI: 1.15\u20131.77) among women. Regarding stroke subtype, hyperuricemia was significantly associated with the incidence (RR\u202f=\u202f1.21, 95%CI: 1.03\u20131.42) and mortality (RR\u202f=\u202f1.23, 95%CI: 1.01\u20131.49) of ischemic stroke. A J shaped dose\u2013response relationship was found between uric acid and stroke incidence (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.0023), with risk rising across uric acid levels from104 to 764.5\u202f\u03bcmol\/L and a nadir at 225\u202f\u03bcmol\/L, whereas no significant nonlinear relationship was observed for stroke mortality.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Hyperuricemia is associated with increased risks of stroke incidence and mortality, especially in women and ischemic stroke. A J-shaped dose\u2013response relationship was observed for stroke incidence, but not for stroke mortality. Monitoring uric acid levels and their longitudinal changes may be valuable in stroke prevention strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420261394403<\/jats:ext-link>\n                      , identifier PROSPERO (CRD420261394403).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1900039","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:40:28Z","timestamp":1787114428000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Evidence for a dose\u2013response association of hyperuricemia with stroke incidence: a meta-analysis of cohort studies"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuening","family":"Liu","sequence":"first","affiliation":[{"name":"School of Nursing, Shandong Second Medical University","place":["Weifang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Nursing Shandong University of Traditional Chinese Medicine","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SaiWei","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Nursing, Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Nursing, The First Affiliated Hospital of Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref1","volume-title":"Stroke [Eb]. Who Fact Sheets","year":"2025"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1177\/17474930211065917","article-title":"World Stroke Organization (WSO): global stroke fact sheet 2022","volume":"17","author":"Feigin","year":"2022","journal-title":"Int J Stroke"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the global burden of disease study 2019","volume":"20","year":"2021","journal-title":"Lancet Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ijcard.2015.08.109","article-title":"Regulation of uric acid metabolism and excretion","volume":"213","author":"Maiuolo","year":"2016","journal-title":"Int J Cardiol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"106432","DOI":"10.1016\/j.ejim.2025.07.028","article-title":"Crystal clear - Part I: the role of uric acid in cardiorenal disease","volume":"142","author":"Borghi","year":"2025","journal-title":"Eur J Intern Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ejim.2015.11.026","article-title":"Uric acid in metabolic syndrome: from an innocent bystander to a central player","volume":"29","author":"Kanbay","year":"2016","journal-title":"Eur J Intern Med"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1080\/15257770802138558","article-title":"Uric acid: the oxidant-antioxidant paradox","volume":"27","author":"Sautin","year":"2008","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1161\/Circresaha.116.308398","article-title":"Stroke risk factors, genetics, and prevention","volume":"120","author":"Boehme","year":"2017","journal-title":"Circ Res"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.atherosclerosis.2013.11.051","article-title":"Hyperuricemia and risk of stroke: a systematic review and meta-analysis of prospective studies","volume":"232","author":"Li","year":"2014","journal-title":"Atherosclerosis"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The Prisma 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2020","journal-title":"BMJ"},{"key":"ref11","volume-title":"Prospero Record: Crd420261394403 [Eb]. Prospero: International Prospective Register of systematic Reviews","year":"2026"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur J Epidemiol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"e56864","DOI":"10.1371\/journal.pone.0056864","article-title":"High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies","volume":"8","author":"Lv","year":"2013","journal-title":"PLoS One"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1053\/j.ajkd.2004.06.006","article-title":"Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort","volume":"44","author":"Iseki","year":"2004","journal-title":"Am J Kidney Dis"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1093\/aje\/kwr265","article-title":"Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software","volume":"175","author":"Orsini","year":"2012","journal-title":"Am J Epidemiol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"403","DOI":"10.2188\/jea.10.403","article-title":"Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers","volume":"10","author":"Tomita","year":"2000","journal-title":"J Epidemiol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1023\/A:1021216713504","article-title":"Predictors of stroke mortality in elderly people from the general population. The cardiovascular study in the elderly","volume":"17","author":"Mazza","year":"2001","journal-title":"Eur J Epidemiol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1097\/01.hjr.0000130222.50258.22","article-title":"Serum uric acid and risk of death from cancer, cardiovascular disease or all causes in men","volume":"11","author":"Jee","year":"2004","journal-title":"Eur J Cardiovasc Prev Rehabil"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.atherosclerosis.2005.01.018","article-title":"Hyperuricemia as a risk factor on cardiovascular events in Taiwan: the Chin-Shan community cardiovascular cohort study","volume":"183","author":"Chien","year":"2005","journal-title":"Atherosclerosis"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1097\/01.hjr.0000192745.26973.00","article-title":"Serum uric acid and long-term mortality from stroke, coronary heart disease and all causes","volume":"13","author":"Gerber","year":"2006","journal-title":"Eur J Cardiovasc Prev Rehabil"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.atherosclerosis.2005.09.020","article-title":"Serum uric acid and risk of ischemic stroke: the Aric study","volume":"187","author":"Hozawa","year":"2006","journal-title":"Atherosclerosis"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1291\/hypres.30.823","article-title":"Fatty liver and uric acid levels predict incident coronary heart disease but not stroke among atomic bomb survivors in Nagasaki","volume":"30","author":"Baba","year":"2007","journal-title":"Hypertens Res"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.ijcard.2007.11.094","article-title":"Serum uric acid is an independent predictor for all major forms of cardiovascular death in 28,613 elderly women: a prospective 21-year follow-up study","volume":"125","author":"Strasak","year":"2008","journal-title":"Int J Cardiol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1111\/j.1365-2796.2009.02133.x","article-title":"Uric acid and risk of myocardial infarction, stroke and congestive heart failure in 417,734 men and women in the apolipoprotein mortality risk study (Amoris)","volume":"266","author":"Holme","year":"2009","journal-title":"J Intern Med"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1093\/rheumatology\/kes223","article-title":"Significance of serum uric acid levels on the risk of all-cause and cardiovascular mortality","volume":"52","author":"Kuo","year":"2013","journal-title":"Rheumatology (Oxford)"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1111\/ene.12998","article-title":"Plasma uric acid concentrations and risk of ischaemic stroke in women","volume":"23","author":"Jim\u00e9nez","year":"2016","journal-title":"Eur J Neurol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"692","DOI":"10.5551\/jat.31591","article-title":"Serum uric acid and mortality form cardiovascular disease: Epoch-Japan study","volume":"23","author":"Zhang","year":"2016","journal-title":"J Atheroscler Thromb"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s10157-016-1311-7","article-title":"Associations between serum uric acid levels and the incidence of nonfatal stroke: a nationwide community-based cohort study","volume":"21","author":"Kamei","year":"2017","journal-title":"Clin Exp Nephrol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1177\/2047487317744045","article-title":"Serum uric acid level predicts adverse outcomes after myocardial revascularization or cardiac valve surgery","volume":"25","author":"Lazzeroni","year":"2018","journal-title":"Eur J Prev Cardiol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1080\/10641963.2017.1281938","article-title":"Prospective study of serum uric acid levels and stroke in a Chinese hypertensive cohort","volume":"39","author":"Shi","year":"2017","journal-title":"Clin Exp Hypertens"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.atherosclerosis.2018.02.003","article-title":"Uric acid is associated with long-term adverse cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention","volume":"270","author":"Tscharre","year":"2018","journal-title":"Atherosclerosis"},{"key":"ref32","volume-title":"A Prospective Cohort Study on the Associations of Serum Uric Acid, Bilirubin, and Their Changes With the Risk of Cardiovascular Disease [D]","author":"Lai","year":"2019"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1038\/s41440-019-0390-8","article-title":"Serum uric acid levels and cardiovascular mortality in a general Japanese population: the Hisayama study","volume":"43","author":"Sakata","year":"2020","journal-title":"Hypertens Res"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41440-019-0385-5","article-title":"Serum uric acid and risk of stroke and its types: the circulatory risk in communities study (Circs)","volume":"43","author":"Li","year":"2020","journal-title":"Hypertens Res"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1161\/Hypertensionaha.119.13580","article-title":"Severity of hypertension mediates the association of hyperuricemia with stroke in the regards case cohort study","volume":"75","author":"Chaudhary","year":"2020","journal-title":"Hypertension"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"3415","DOI":"10.1016\/j.numecd.2021.08.043","article-title":"High-level uric acid in asymptomatic hyperuricemia could be an isolated risk factor of cardio-cerebrovascular diseases: a prospective cohort study","volume":"31","author":"Cheng","year":"2021","journal-title":"Nutr Metab Cardiovasc Dis"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"807420","DOI":"10.3389\/fphys.2021.807420","article-title":"Prospective study of serum uric acid levels and first stroke events in Chinese adults with hypertension","volume":"12","author":"Hu","year":"2021","journal-title":"Front Physiol"},{"key":"ref38","volume-title":"Study on the Relationship Between Uric Acid and Its Changes and Ischemic Stroke in a Community-Based Hypertensive Population [D]","author":"Tan","year":"2022"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1599730","DOI":"10.3389\/fneur.2025.1599730","article-title":"Inflammation mediates the association between hyperuricemia and stroke mortality: a cohort study","volume":"16","author":"He","year":"2025","journal-title":"Front Neurol"},{"key":"ref40","volume-title":"Association Analysis Between Uric Acid and Ischemic Stroke: An Observational Study and Mendelian Randomization Study","author":"Zhang","year":"2025"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.5049\/Ebp.2014.12.1.1","article-title":"Uric acid puzzle: dual role as anti-oxidantand pro-oxidant","volume":"12","author":"Kang","year":"2014","journal-title":"Electrolyte Blood Press"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"3188","DOI":"10.3390\/ijms23063188","article-title":"Uric acid and oxidative stress-relationship with cardiovascular, metabolic, and renal impairment","volume":"23","author":"Gherghina","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1006\/abbi.2000.1721","article-title":"Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid","volume":"376","author":"Squadrito","year":"2000","journal-title":"Arch Biochem Biophys"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"221","DOI":"10.3164\/jcbn.20-94","article-title":"Serum uric acid and risk of stroke: a dose-response meta-analysis","volume":"68","author":"Dong","year":"2021","journal-title":"J Clin Biochem Nutr"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"3","DOI":"10.5853\/jos.2016.00864","article-title":"Epidemiology, risk factors, and clinical features of intracerebral Hemorrhage: an update","volume":"19","author":"An","year":"2017","journal-title":"J Stroke"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"112","DOI":"10.18678\/dtfd.1457023","article-title":"Evaluation of the association of serum uric acid levels and stroke in emergency department patients","volume":"26","author":"\u015eeng\u00fcld\u00fcr","year":"2024","journal-title":"Duzce Med J"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"e41105","DOI":"10.1097\/Md.0000000000041105","article-title":"Prevalence and clinical significance of hypouricemia in the emergency department","volume":"103","author":"\u015eeng\u00fcld\u00fcr","year":"2024","journal-title":"Medicine (Baltimore)"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1038\/s41371-024-00906-5","article-title":"Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of xilo-fist","volume":"38","author":"Macdonald","year":"2024","journal-title":"J Hum Hypertens"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/j.jfma.2025.05.040","article-title":"Cardiovascular outcomes of febuxostat and allopurinol: a long-term Taiwanese nationwide cohort study","volume":"125","author":"Yang","year":"2026","journal-title":"J Formos Med Assoc"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"2470478","DOI":"10.1080\/0886022X.2025.2470478","article-title":"Comparative efficacy and safety of febuxostat and allopurinol in chronic kidney disease stage 3-5 patients with asymptomatic hyperuricemia: a network meta-analysis","volume":"47","author":"Chen","year":"2025","journal-title":"Ren Fail"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1900039\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:40:43Z","timestamp":1787114443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1900039\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":50,"alternative-id":["10.3389\/fneur.2026.1900039"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1900039","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"article-number":"1900039"}}