{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:24:28Z","timestamp":1792589068789,"version":"4.5.0"},"reference-count":76,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Arteriolosclerotic cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia, yet no disease\u2010modifying therapies exist. Anti\u2010inflammatory strategies targeting IL\u20106 (interleukin\u20106) signaling have shown efficacy in preventing atherosclerotic cardiovascular disease, but their potential in arteriolosclerotic cSVD remains unexplored. We investigated whether genetically downregulated IL\u20106 signaling is associated with clinical, imaging, and pathological manifestations of arteriolosclerotic cSVD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We applied 2\u2010sample Mendelian randomization using (1) 26 genetic variants near\n                      <jats:italic toggle=\"no\">IL6R<\/jats:italic>\n                      (interleukin\u20106 receptor) associated with circulating C\u2010reactive protein levels and (2) rs2228145, a well\u2010characterized\n                      <jats:italic toggle=\"no\">IL6R<\/jats:italic>\n                      missense variant, as proxies of IL\u20106 signaling downregulation. Outcomes included clinical (small vessel stroke, magnetic resonance imaging\u2010defined lacunar stroke, nonlobar intracerebral hemorrhage, vascular dementia), imaging (white matter hyperintensity volume, extensive basal ganglia perivascular space, nonlobar\/mixed cerebral microbleeds), and pathological (arteriolosclerosis burden in autopsy) traits of cSVD, as well as atherosclerosis traits (ultrasound\u2010defined carotid plaque, large artery stroke) as positive controls. We used inverse\u2010variance weighting and the Wald ratio estimator for primary analyses. Mendelian randomization\u2010Egger regression, weighted median, and weighted mode estimators were used as sensitivity analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Genetically downregulated IL\u20106 signaling (30% decrement in C\u2010reactive protein via 26\n                      <jats:italic toggle=\"no\">IL6R<\/jats:italic>\n                      variants) was not associated with small vessel stroke (odds ratio [OR], 1.02 [95% CI, 0.95\u20131.10]), magnetic resonance imaging\u2010confirmed lacunar stroke (OR, 0.95, [95% CI, 0.81\u20131.11]), nonlobar intracerebral hemorrhage (OR, 1.04 [95% CI, 0.72\u20131.50]), or vascular dementia (OR, 1.09 [95% CI, 0.95\u20131.25]). Similarly, we found no significant association with cSVD imaging biomarkers or pathology\u2010defined arteriolosclerosis. As expected, genetically downregulated IL\u20106 signaling was associated with lower odds of large artery stroke (OR, 0.79 [95% CI, 0.74\u20130.84]) and carotid plaque (OR, 0.88 [95% CI, 0.83\u20130.94]). Results were consistent across sensitivity analyses and when using the rs2228145 missense variant to proxy IL\u20106 signaling downregulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Unlike atherosclerotic traits, genetically proxied IL\u20106 signaling downregulation is not associated with clinical, imaging, or pathological manifestations of arteriolosclerotic cSVD. These genetic findings suggest that targeting IL\u20106 signaling is unlikely to yield effects on cSVD prevention comparable with those expected for atherosclerotic disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.041814","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T13:16:27Z","timestamp":1762175787000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic Downregulation of Interleukin\u20106 Signaling and Arteriolosclerotic Cerebral Small Vessel Disease: A Drug Target Mendelian Randomization Analysis"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9591-6139","authenticated-orcid":false,"given":"Larissa Ange","family":"Tchuisseu\u2010Kwangoua","sequence":"first","affiliation":[{"name":"University of Oxford","place":["Oxford, UK"]},{"name":"University of Yaound\u00e9 1","place":["Yaound\u00e9, Cameroon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6126-8631","authenticated-orcid":false,"given":"Murad","family":"Omarov","sequence":"additional","affiliation":[{"name":"LMU Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Shatunov","sequence":"additional","affiliation":[{"name":"University of Cambridge","place":["Oxford, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9794-5996","authenticated-orcid":false,"given":"Hugh S.","family":"Markus","sequence":"additional","affiliation":[{"name":"University of Cambridge","place":["Oxford, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1041-4202","authenticated-orcid":false,"given":"Joseph","family":"Kamtchum\u2010Tatuene","sequence":"additional","affiliation":[{"name":"University of Oxford","place":["Oxford, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-3659","authenticated-orcid":false,"given":"Marios K.","family":"Georgakis","sequence":"additional","affiliation":[{"name":"LMU Munich","place":["Munich, Germany"]},{"name":"Broad Institute of MIT and Harvard","place":["Cambridge, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60371-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200105103441907"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308426"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00463-8"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.04.034"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2018.3122"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007142"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.70.1.9"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70060-7"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30079-1"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0014-y"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007654"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/svn-2016-000035"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.121.319077"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021372"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912388"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02235-6"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2019.100916"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)00968-1"},{"key":"e_1_3_2_22_2","unstructured":"Amarenco P. Evaluation of Low Dose Colchicine and Ticagrelor in Prevention of Ischemic Stroke in Patients With Stroke Due to Atherosclerosis (RIISC\u2010THETIS). 2022. Accessed November 25 2024. https:\/\/clinicaltrials.gov\/study\/NCT05476991."},{"key":"e_1_3_2_23_2","unstructured":"Keech T. Colchicine After Stroke Event to Prevent Event Recurrence (CASPER): A Randomised Trial to Evaluate the Efficacy of Oral Colchicine in High\u2010Risk Patients With Atherosclerosis\u2010Associated Inflammation Post\u2010Stroke. 2021. Accessed November 25 2024. https:\/\/www.anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?id=382337&showOriginal=true&isReview=true."},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07316-0"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61931-4"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60110-X"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.023277"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.052604"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.319589"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002872"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.123.064974"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-022-02446-6"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz542"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.320877"},{"key":"e_1_3_2_35_2","unstructured":"Novo Nordisk . ZEUS\u2014A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease Chronic Kidney Disease and Inflammation (ZEUS). 2021. Accessed November 25 2024. https:\/\/clinicaltrials.gov\/study\/NCT05021835."},{"key":"e_1_3_2_36_2","unstructured":"Novo Nordisk . A Research Study Looking Into How Ziltivekimab Works Compared to Placebo in Participants With Heart Failure and Inflammation (ATHENA). 2023. Accessed 25 Nov 2024. https:\/\/clinicaltrials.gov\/study\/NCT06200207."},{"key":"e_1_3_2_37_2","unstructured":"Novo Nordisk . A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation (HERMES). 2022. Accessed November 25 2024. https:\/\/clinicaltrials.gov\/study\/NCT05636176."},{"key":"e_1_3_2_38_2","unstructured":"Novo Nordisk . ARTEMIS\u2014A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With a Heart Attack (ARTEMIS). 2023. Accessed November 25 2024. https:\/\/clinicaltrials.gov\/study\/NCT06118281."},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.18236"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n2233"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29650-5"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.05.018"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003444"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3583"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9111"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2019.11.001"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.24.1.35"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05165-3"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0058-3"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.111.613752"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0136352"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.02.012"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-01035-w"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14115"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19111-2"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02268-w"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00131-X"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000010852"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01939-9"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12365"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1159\/000343145"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","unstructured":"Omarov M Zhang L Doroodgar Jorshery S Malik R Das B Bellomo TR Mansmann U Menten MJ Natarajan P Dichgans M et\u00a0al. Deep learning\u2010based detection of carotid plaques informs cardiovascular risk prediction and reveals genetic drivers of atherosclerosis. 2024. medRxiv. 2024.2010.2017.24315675. 10.1101\/2024.10.17.24315675.","DOI":"10.1101\/2024.10.17.24315675"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21758"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwy185"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyv080"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyx102"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1177\/0962280215597579"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyr036"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26332"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyt179"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1552-6569.2007.00150.x"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.107.699785"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1586\/14737175.2014.884926"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21998"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.124.041814","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:21:37Z","timestamp":1780485697000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.124.041814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,4]]},"references-count":76,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2025,11,4]]}},"alternative-id":["10.1161\/JAHA.124.041814"],"URL":"https:\/\/doi.org\/10.1161\/jaha.124.041814","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,4]]},"assertion":[{"value":"2025-02-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e041814"}}