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Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study.

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cam.issuedOnline2022-03-21
dc.contributor.authorSoremekun, Opeyemi
dc.contributor.authorKarhunen, Ville
dc.contributor.authorHe, Yiyan
dc.contributor.authorRajasundaram, Skanda
dc.contributor.authorLiu, Bowen
dc.contributor.authorGkatzionis, Apostolos
dc.contributor.authorSoremekun, Chisom
dc.contributor.authorUdosen, Brenda
dc.contributor.authorMusa, Hanan
dc.contributor.authorSilva, Sarah
dc.contributor.authorKintu, Christopher
dc.contributor.authorMayanja, Richard
dc.contributor.authorNakabuye, Mariam
dc.contributor.authorMachipisa, Tafadzwa
dc.contributor.authorMason, Amy
dc.contributor.authorVujkovic, Marijana
dc.contributor.authorZuber, Verena
dc.contributor.authorSoliman, Mahmoud
dc.contributor.authorMugisha, Joseph
dc.contributor.authorNash, Oyekanmi
dc.contributor.authorKaleebu, Pontiano
dc.contributor.authorNyirenda, Moffat
dc.contributor.authorChikowore, Tinashe
dc.contributor.authorNitsch, Dorothea
dc.contributor.authorBurgess, Stephen
dc.contributor.authorGill, Dipender
dc.contributor.authorFatumo, Segun
dc.contributor.orcidMason, Amy [0000-0002-8019-0777]
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
dc.date.accessioned2022-04-25T01:02:44Z
dc.date.available2022-04-25T01:02:44Z
dc.date.issued2022-04
dc.date.updated2022-04-25T01:02:43Z
dc.description.abstractBACKGROUND: Dyslipidaemia is highly prevalent in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have sought to disentangle the causal relationship between dyslipidaemia and T2DM liability. However, conventional observational studies are vulnerable to confounding. Mendelian Randomization (MR) studies (which address this bias) on lipids and T2DM liability have focused on European ancestry individuals, with none to date having been performed in individuals of African ancestry. We therefore sought to use MR to investigate the causal effect of various lipid traits on T2DM liability in African ancestry individuals. METHODS: Using univariable and multivariable two-sample MR, we leveraged summary-level data for lipid traits and T2DM liability from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612, 36.9% men) and from African ancestry individuals in the Million Veteran Program (Ncases = 23,305 and Ncontrols = 30,140, 87.2% men), respectively. Genetic instruments were thus selected from the APCDR after which they were clumped to obtain independent instruments. We used a random-effects inverse variance weighted method in our primary analysis, complementing this with additional sensitivity analyses robust to the presence of pleiotropy. FINDINGS: Increased genetically proxied low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were associated with increased T2DM liability in African ancestry individuals (odds ratio (OR) [95% confidence interval, P-value] per standard deviation (SD) increase in LDL-C = 1.052 [1.000 to 1.106, P = 0.046] and per SD increase in TC = 1.089 [1.014 to 1.170, P = 0.019]). Conversely, increased genetically proxied high-density lipoprotein cholesterol (HDL-C) was associated with reduced T2DM liability (OR per SD increase in HDL-C = 0.915 [0.843 to 0.993, P = 0.033]). The OR on T2DM per SD increase in genetically proxied triglyceride (TG) levels was 0.884 [0.773 to 1.011, P = 0.072] . With respect to lipid-lowering drug targets, we found that genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with increased T2DM liability (OR per SD decrease in genetically proxied LDL-C = 1.68 [1.03-2.72, P = 0.04]) but we did not find evidence of a relationship between genetically proxied proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and T2DM liability. INTERPRETATION: Consistent with MR findings in Europeans, HDL-C exerts a protective effect on T2DM liability and HMGCR inhibition increases T2DM liability in African ancestry individuals. However, in contrast to European ancestry individuals, LDL-C may increase T2DM liability in African ancestry individuals. This raises the possibility of ethnic differences in the metabolic effects of dyslipidaemia in T2DM. FUNDING: See the Acknowledgements section for more information.
dc.identifier.doi10.17863/CAM.83820
dc.identifier.eissn2352-3964
dc.identifier.issn2352-3964
dc.identifier.other35325778
dc.identifier.otherPMC8941323
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/336403
dc.languageeng
dc.language.isoeng
dc.publisherElsevier BV
dc.publisher.urlhttp://dx.doi.org/10.1016/j.ebiom.2022.103953
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourcenlmid: 101647039
dc.sourceessn: 2352-3964
dc.subjectHMGCR
dc.subjectLipid traits
dc.subjectMendelian Randomization
dc.subjectPCSK9
dc.subjectType 2 diabetes mellitus
dc.subjectCholesterol, HDL
dc.subjectCholesterol, LDL
dc.subjectDiabetes Mellitus, Type 2
dc.subjectFemale
dc.subjectGenome-Wide Association Study
dc.subjectHumans
dc.subjectMale
dc.subjectMendelian Randomization Analysis
dc.subjectPolymorphism, Single Nucleotide
dc.subjectProprotein Convertase 9
dc.subjectRisk Factors
dc.titleLipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study.
dc.typeArticle
dcterms.dateAccepted2022-03-08
prism.publicationNameEBioMedicine
prism.volume78
pubs.funder-project-idWellcome Trust (204623/Z/16/Z)
pubs.funder-project-idMedical Research Council (MC_UU_00002/7)
pubs.funder-project-idNational Institute for Health and Care Research (IS-BRC-1215-20014)
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1016/j.ebiom.2022.103953

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