Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study.
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Authors
Soremekun, Opeyemi
Karhunen, Ville
He, Yiyan
Rajasundaram, Skanda
Liu, Bowen
Gkatzionis, Apostolos
Soremekun, Chisom
Udosen, Brenda
Musa, Hanan
Silva, Sarah
Kintu, Christopher
Mayanja, Richard
Nakabuye, Mariam
Machipisa, Tafadzwa
Vujkovic, Marijana
Zuber, Verena
Soliman, Mahmoud
Mugisha, Joseph
Nash, Oyekanmi
Kaleebu, Pontiano
Nyirenda, Moffat
Chikowore, Tinashe
Nitsch, Dorothea
Gill, Dipender
Fatumo, Segun
Publication Date
2022-04Journal Title
EBioMedicine
ISSN
2352-3964
Publisher
Elsevier BV
Volume
78
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Soremekun, O., Karhunen, V., He, Y., Rajasundaram, S., Liu, B., Gkatzionis, A., Soremekun, C., et al. (2022). Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study.. EBioMedicine, 78 https://doi.org/10.1016/j.ebiom.2022.103953
Abstract
BACKGROUND: 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.
Keywords
Type 2 diabetes mellitus, Mendelian Randomization, Pcsk9, Hmgcr, Lipid Traits
Sponsorship
Wellcome Trust (204623/Z/16/Z)
Medical Research Council (MC_UU_00002/7)
National Institute for Health Research (IS-BRC-1215-20014)
Identifiers
35325778, PMC8941323
External DOI: https://doi.org/10.1016/j.ebiom.2022.103953
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336403
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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