{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:01:49Z","timestamp":1784768509218,"version":"3.55.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,1,4]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Although trials suggest that anti\u2010inflammatory approaches targeting interleukin (IL)\u20106 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL\u20106 signaling could reduce risk additively to low\u2010density lipoprotein cholesterol (LDL\u2010C) lowering. Here, we assess interactions in associations of genetic downregulation of IL\u20106 signaling and LDL\u2010C lowering with lifetime cardiovascular disease risk.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Genetic scores for IL\u20106 signaling downregulation and LDL\u2010C lowering were used to divide 408\u00a0225 White British individuals in UK Biobank into groups of lifelong exposure to downregulated IL\u20106 signaling, lower LDL\u2010C, or both. Associations with risk of cardiovascular disease (coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, vascular death) were explored in factorial Mendelian randomization. Compared with individuals with genetic IL\u20106 and LDL\u2010C scores above the median, individuals with LDL\u2010C scores lower than the median but IL\u20106 scores above the median had an odds ratio (OR) of 0.96 (95% CI, 0.93\u20130.98) for cardiovascular disease. A similar OR (0.96; 95% CI, 0.93\u20130.98) was estimated for individuals with genetic IL\u20106 scores below the median but LDL\u2010C scores above the median. Individuals with both genetic scores lower than the median were at lower odds of cardiovascular disease (OR, 0.92; 95% CI, 0.90\u20130.95). There was no interaction between the 2 scores (relative excess risk attributed to interaction index, 0; synergy index, 1;\n              <jats:italic>P<\/jats:italic>\n              for multiplicative interaction=0.51). Genetic IL\u20106 score below the median was associated with lower cardiovascular disease risk across measured LDL\u2010C strata (&lt;100 or \u2265100\u00a0mg\/dL).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Genetically downregulated IL\u20106 signaling and genetically lowered LDL\u2010C are associated with additively lower lifetime risk of cardiovascular disease. Future trials should explore combined IL\u20106 inhibition and LDL\u2010C lowering treatments for cardiovascular prevention.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.121.023277","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T13:03:06Z","timestamp":1640005386000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Additive Effects of Genetic Interleukin\u20106 Signaling Downregulation and Low\u2010Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2\u00d72 Factorial Mendelian Randomization Analysis"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3507-3659","authenticated-orcid":false,"given":"Marios K.","family":"Georgakis","sequence":"first","affiliation":[{"name":"Institute for Stroke and Dementia Research University Hospital Ludwig\u2010Maximilians\u2010University Munich Germany"},{"name":"Center for Genomic Medicine Massachusetts General HospitalHarvard Medical School Boston MA"},{"name":"Program in Medical and Population Genetics Broad Institute of Massachusetts Institute of Technology and Harvard Cambridge MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-2520","authenticated-orcid":false,"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research University Hospital Ludwig\u2010Maximilians\u2010University Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-8760","authenticated-orcid":false,"given":"Stephen","family":"Burgess","sequence":"additional","affiliation":[{"name":"Cardiovascular Epidemiology Unit University of Cambridge United Kingdom"},{"name":"MRC Biostatistics Unit University of Cambridge United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0654-387X","authenticated-orcid":false,"given":"Martin","family":"Dichgans","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research University Hospital Ludwig\u2010Maximilians\u2010University Munich Germany"},{"name":"Munich Cluster for Systems Neurology (SyNergy) Munich Germany"},{"name":"German Centre for Neurodegenerative Diseases Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1912388"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021372"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60110-X"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002872"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.052604"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00520-1"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.1.64"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0807646"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313129"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz413"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.11467"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyz161"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy310"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex423"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2797"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.09.009"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11122"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306656"},{"key":"e_1_3_2_23_2","first-page":"660506","article-title":"Genetics of 38 blood and urine biomarkers in the UK Biobank","author":"Sinnott\u2010Armstrong N","year":"2019","unstructured":"Sinnott\u2010Armstrong N, Tanigawa Y, Amar D, Mars NJ, Aguirre M, Venkataraman GR, Wainberg M, Ollila HM, Pirruccello JP, Qian J, et al. Genetics of 38 blood and urine biomarkers in the UK Biobank. bioRxiv. 2019:660506. 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