Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management

EBioMedicine

卷:80

Kent R. Heberer¹  Venexia M. Walker²  Donald R. Miller³  Megan M. Shuey⁴  Jacob M. Keaton⁵  Marijana Vujkovic⁶  Nikhil K. Khankari⁷  Kyung Min Lee⁸  Shoa L. Clarke⁹  Peter D. Reaven¹⁰  Todd L. Edwards¹¹  Julie A. Lynch¹² 

[1] Bristol Medical School: Population Health Sciences, University of Bristol, Bristol, UK;

[2] Corresponding author at: Dr. Nikhil K. Khankari, Division of Genetic Medicine, Vanderbilt University Medical Center, 2525 West End Ave, Suite 700, Nashville, TN 37203, USA.;

[3] Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA;

[4] Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;

[5] Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 2525 West End Ave, Suite 700, Nashville, TN 37203, USA;

[6] Departments of Medicine and Pediatrics, Stanford University School of Medicine, Stanford, CA, USA;

[7] Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA;

[8] Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA;

[9] Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, UK;

[10] VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA;

[11] VA Palo Alto Health Care System, Palo Alto, CA, USA;

关键词: Mendelian randomisation;    Lipids;    Statins;    Icosapent ethyl;    Gene expression;    Type 2 diabetes;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: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.

【 授权许可】

Unknown