University of Oulu

Soremekun, O., Karhunen, V., He, Y., Rajasundaram, S., Liu, B., Gkatzionis, A., Soremekun, C., Udosen, B., Musa, H., Silva, S., Kintu, C., Mayanja, R., Nakabuye, M., Machipisa, T., Mason, A., Vujkovic, M., Zuber, V., Soliman, M., Mugisha, J., … Fatumo, S. (2022). Lipid traits and type 2 diabetes risk in African ancestry individuals: A Mendelian Randomization study. EBioMedicine, 78, 103953. https://doi.org/10.1016/j.ebiom.2022.103953

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

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Author: Soremekun, Opeyemi1; Karhunen, Ville2,3; He, Yiyan2;
Organizations: 1The African Computational Genomics (TACG) Research group, MRC/UVRI and LSHTM, Entebbe, Uganda
2Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
3Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
4Kellogg College, University of Oxford, Oxford, UK
5Faculty of Medicine, Imperial College London, London, UK
6MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, UK
7MRC Integrative Epidemiology Unit, University of Bristol, UK
8Population Health Sciences, Bristol Medical School, University of Bristol, UK
9Department of Non-communicable Disease Epidemiology (NCDE), London School of Hygiene and Tropical Medicine, London, UK
10Department of Medicine, University of Cape Town & Groote Schuur Hospital, Cape Town, South Africa
11Department of Medicine, Hatter Institute for Cardiovascular Diseases Research in Africa (HICRA) & Cape Heart Institute (CHI), University of Cape Town, South Africa
12Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada
13Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
14Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
15Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
16Department of Epidemiology and Biostatistics, Medical School Building, St Mary’s Hospital, Imperial College London, London, UK
17Discipline of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
18MRC/UVRI and LSHTM, Entebbe, Uganda
19H3Africa Bioinformatics Network (H3ABioNet) Node, Centre for Genomics Research and Innovation, NABDA/FMST, Abuja, Nigeria
20Department of Pediatrics, MRC/Wits Developmental Pathways for Health Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
21Faculty of Health Sciences, Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa
22Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
23Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.4 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022050532807
Language: English
Published: Elsevier, 2022
Publish Date: 2022-06-20
Description:

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.

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Series: EBioMedicine
ISSN: 2352-3964
ISSN-E: 2352-3964
ISSN-L: 2352-3964
Volume: 78
Article number: 103953
DOI: 10.1016/j.ebiom.2022.103953
OADOI: https://oadoi.org/10.1016/j.ebiom.2022.103953
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3142 Public health care science, environmental and occupational health
Subjects:
Funding: SF is an international Intermediate Fellow funded by the Wellcome Trust grant (220740/Z/20/Z) at the MRC/UVRI and LSHTM. TC is an international training fellow supported by the Wellcome Trust grant (214205/Z/18/Z). DG was supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College, and a National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St. George's, University of London. VK is supported by the Academy of Finland Project 312123, and European Union's Horizon 2020 research and innovation programme under Grant Agreement No 848158 (EarlyCause). M. Nakabuye acknowledges the support of Makerere University Non-Communicable Diseases (MacNCD). This research is made possible by the MakNCD Research Training Program: National Institutes of Health (NIH) 1D43TW011401-01 through the Fogarty International Center (FIC). C Soremekun, B. Udosen, and S Fatumo acknowledge H3Africa Bioinformatics Network (H3ABioNet) Node, National Biotechnology Development Agency (NABDA), and the Center for Genomics Research and Innovation (CGRI) Abuja, Nigeria. Dr Mason is funded by the EC-Innovative Medicines Initiative (BigData@Heart). Dr Burgess is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z). This research was funded by UK Research and Innovation (UKRI) Medical Research Council (MC_UU_00002/7) and supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funding sources did not have any role in designing the study, performing analysis, or communicating findings.
EU Grant Number: (848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity
Academy of Finland Grant Number: 312123
Detailed Information: 312123 (Academy of Finland Funding decision)
Copyright information: © 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
  https://creativecommons.org/licenses/by-nc-nd/4.0/