@article{8f671660f3e1421cbe7c589340239320,
title = "Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management",
abstract = "Background: Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. Methods: Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). Findings: IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. Interpretation: Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. Funding: Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments.",
keywords = "Drug repurposing, Gene expression, Icosapent ethyl, Lipids, Mendelian randomisation, Statins, Type 2 diabetes",
author = "Khankari, {Nikhil K.} and Keaton, {Jacob M.} and Walker, {Venexia M.} and Lee, {Kyung Min} and Shuey, {Megan M.} and Clarke, {Shoa L.} and Heberer, {Kent R.} and Miller, {Donald R.} and Reaven, {Peter D.} and Lynch, {Julie A.} and Marijana Vujkovic and Edwards, {Todd L.}",
note = "Funding Information: We would like to acknowledge the Million Veteran Program (MVP) participants. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH), and by National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS). The GTEx data used for this were obtained from dbGaP Accession number phs000424v7p2. GWAS summary statistics were for lipid traits were downloaded from the Global Lipids Genetics Consortium ( http://csg.sph.umich.edu//abecasis/public/lipids2013 ). GWAS summary statistics for the negative control trait (natural hair color) were downloaded from the UK Biobank (dataset: ukb-d-1747_5; https://gwas.mrcieu.ac.uk/datasets/ ). We want to acknowledge the participants and investigators of FinnGen study ( https://finngen.gitbook.io/documentation/ ). NKK is supported by NIH R00 CA215360. VMW is supported by the MRC Integrative Epidemiology Unit at the University of Bristol (MC UU 00011/1 and MC UU 00011/4). Funding Information: We would like to acknowledge the Million Veteran Program (MVP) participants. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH), and by National Cancer Institute (NCI), National Human Genome Research Institute (NHGRI), National Heart, Lung, and Blood Institute (NHLBI), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS). The GTEx data used for this were obtained from dbGaP Accession number phs000424v7p2. GWAS summary statistics were for lipid traits were downloaded from the Global Lipids Genetics Consortium (http://csg.sph.umich.edu//abecasis/public/lipids2013). GWAS summary statistics for the negative control trait (natural hair color) were downloaded from the UK Biobank (dataset: ukb-d-1747_5; https://gwas.mrcieu.ac.uk/datasets/). We want to acknowledge the participants and investigators of FinnGen study (https://finngen.gitbook.io/documentation/). NKK is supported by NIH R00 CA215360. VMW is supported by the MRC Integrative Epidemiology Unit at the University of Bristol (MC UU 00011/1 and MC UU 00011/4). Our analysis utilized only summary statistics from published GWAS. All GPGE summary statistics used in our analysis are provided in the Supplementary Materials. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = jun,
doi = "10.1016/j.ebiom.2022.104038",
language = "English (US)",
volume = "80",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}