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Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis.

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cam.issuedOnline2021-12-20
cam.orpheus.counter3
cam.orpheus.successTue Feb 01 19:02:10 GMT 2022 - Embargo updated
dc.contributor.authorGeorgakis, Marios K
dc.contributor.authorMalik, Rainer
dc.contributor.authorBurgess, Stephen
dc.contributor.authorDichgans, Martin
dc.contributor.orcidGeorgakis, Marios K [0000-0003-3507-3659]
dc.contributor.orcidMalik, Rainer [0000-0001-9212-2520]
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
dc.contributor.orcidDichgans, Martin [0000-0002-0654-387X]
dc.date.accessioned2021-11-06T00:30:26Z
dc.date.available2021-11-06T00:30:26Z
dc.date.issued2022-01-04
dc.description.abstractBackground Although trials suggest that anti-inflammatory approaches targeting interleukin (IL)-6 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL-6 signaling could reduce risk additively to low-density lipoprotein cholesterol (LDL-C) lowering. Here, we assess interactions in associations of genetic downregulation of IL-6 signaling and LDL-C lowering with lifetime cardiovascular disease risk. Methods and Results Genetic scores for IL-6 signaling downregulation and LDL-C lowering were used to divide 408 225 White British individuals in UK Biobank into groups of lifelong exposure to downregulated IL-6 signaling, lower LDL-C, 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-6 and LDL-C scores above the median, individuals with LDL-C scores lower than the median but IL-6 scores above the median had an odds ratio (OR) of 0.96 (95% CI, 0.93-0.98) for cardiovascular disease. A similar OR (0.96; 95% CI, 0.93-0.98) was estimated for individuals with genetic IL-6 scores below the median but LDL-C 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, 0.90-0.95). There was no interaction between the 2 scores (relative excess risk attributed to interaction index, 0; synergy index, 1; P for multiplicative interaction=0.51). Genetic IL-6 score below the median was associated with lower cardiovascular disease risk across measured LDL-C strata (<100 or ≥100 mg/dL). Conclusions Genetically downregulated IL-6 signaling and genetically lowered LDL-C are associated with additively lower lifetime risk of cardiovascular disease. Future trials should explore combined IL-6 inhibition and LDL-C lowering treatments for cardiovascular prevention.
dc.identifier.doi10.17863/CAM.77800
dc.identifier.eissn2047-9980
dc.identifier.issn2047-9980
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330357
dc.language.isoeng
dc.publisherOvid Technologies (Wolters Kluwer Health)
dc.publisher.urlhttp://dx.doi.org/10.1161/jaha.121.023277
dc.rightsAll rights reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.subjectMendelian randomization
dc.subjectatherosclerosis
dc.subjectinflammation
dc.subjectinterleukin‐6
dc.subjectlow‐density lipoprotein
dc.subjectCardiovascular Diseases
dc.subjectCholesterol, LDL
dc.subjectDown-Regulation
dc.subjectHumans
dc.subjectInterleukin-6
dc.subjectMendelian Randomization Analysis
dc.subjectRisk Factors
dc.titleAdditive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis.
dc.typeArticle
dcterms.dateAccepted2021-11-02
prism.publicationNameJ Am Heart Assoc
pubs.funder-project-idMedical Research Council (MC_UU_00002/7)
pubs.funder-project-idWellcome Trust (204623/Z/16/Z)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idBritish Heart Foundation (CH/12/2/29428)
pubs.funder-project-idBritish Heart Foundation (RG/18/13/33946)
rioxxterms.licenseref.startdate2021-11-02
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1161/JAHA.121.023277

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