{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:03:25Z","timestamp":1784127805665,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"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":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Observational studies have consistently reported associations between serum uric acid (SUA) and post\u2010stroke epilepsy (PSE) in acute ischemic stroke (AIS), including a recently published large cohort study identifying a U\u2010shaped relationship. However, whether these associations reflect causality and whether SUA provides incremental predictive value beyond established clinical factors remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      we conducted a two\u2010sample Mendelian randomization (\n                      <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n                      ) analysis to test whether lifelong genetically predicted serum urate shares a genetic causal architecture with general epilepsy susceptibility, using 299 independent genetic instruments. In parallel, we performed a prespecified secondary analysis of a multicenter\n                      <jats:styled-content style=\"fixed-case\">AIS<\/jats:styled-content>\n                      cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200921,459) using multivariable logistic regression with restricted cubic splines (\n                      <jats:styled-content style=\"fixed-case\">RCS<\/jats:styled-content>\n                      ) to characterize the observational\n                      <jats:styled-content style=\"fixed-case\">SUA<\/jats:styled-content>\n                      \u2013\n                      <jats:styled-content style=\"fixed-case\">PSE<\/jats:styled-content>\n                      relationship. Formal sex interaction testing (Wald tests) and sex\u2010stratified spline analyses were performed. Predictive utility was evaluated through discrimination (\n                      <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content>\n                      ), calibration, decision curve analysis (\n                      <jats:styled-content style=\"fixed-case\">DCA<\/jats:styled-content>\n                      ), and internal validation with 1000 bootstrap resamples. The two analytical components address related but distinct biological questions: observational analysis tests the admission\u2010\n                      <jats:styled-content style=\"fixed-case\">SUA<\/jats:styled-content>\n                      \u2010to\u20101\u2010year\u2010\n                      <jats:styled-content style=\"fixed-case\">PSE<\/jats:styled-content>\n                      pathway, while\n                      <jats:styled-content style=\"fixed-case\">MR<\/jats:styled-content>\n                      tests whether lifelong genetically predicted urate shares a causal architecture with general epilepsy susceptibility.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MR analysis found no evidence supporting a shared lifelong genetic causal architecture between serum urate and general epilepsy susceptibility across all four methods (IVW: OR\u2009=\u20091.043, 95% CI 0.926\u20131.174,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.487; MR\u2010Egger\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.582; weighted median\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.589; weighted mode\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.996), with no pleiotropy (Egger intercept\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.865) or heterogeneity (Cochran Q\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.206). In the observational cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200921,459; 936 PSE events (4.36%)), RCS analyses confirmed a significant nonlinear SUA\u2013PSE association (P for nonlinearity &lt;\u20090.001). Importantly, a formal sex\u2010by\u2010SUA interaction revealed strikingly divergent patterns (overall\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001; nonlinear component\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0002): Women in the highest SUA tertile had markedly elevated PSE risk (adjusted OR\u2009=\u20092.33, 95% CI 1.71\u20133.19), a finding confirmed with sex\u2010specific tertile cut\u2010points (OR\u2009=\u20091.50,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.005). The apparent protective association in men using overall tertiles (OR\u2009=\u20090.36, 95% CI 0.28\u20130.46) was attenuated and non\u2010significant with sex\u2010specific cut\u2010points (OR\u2009=\u20090.84,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.16), indicating sensitivity to stratification method. Adding SUA to a base clinical model produced a modest but statistically significant increment in discrimination (AUC: 0.8498 to 0.8607, \u0394AUC\u2009=\u20090.011, DeLong\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.001) with consistent positive net benefit on DCA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Genetically predicted lifelong SUA does not share a causal genetic architecture with general epilepsy susceptibility; this null does not exclude acute post\u2010stroke, context\u2010specific mechanisms, which operate on biological timescales outside the scope of Mendelian randomization. The sex\u2010dependent observational association (female high\u2010SUA OR\u2009=\u20091.50 with sex\u2010specific tertiles; sex \u00d7 SUA continuous interaction\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20093.99\u2009\u00d7\u200910\n                      <jats:sup>\u22129<\/jats:sup>\n                      ) generates the hypothesis that sex\u2010stratified SUA monitoring merits prospective investigation, pending external validation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70970","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T14:51:56Z","timestamp":1780930316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Serum Uric Acid as a Sex\u2010Dependent Risk Marker of Post\u2010Stroke Epilepsy After Acute Ischemic Stroke: Complementary Mendelian Randomization and Cohort 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