Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management
Nikhil K. Khankari,
Jacob M. Keaton,
Venexia M. Walker,
Kyung Min Lee,
Megan M. Shuey,
Shoa L. Clarke,
Kent R. Heberer,
Donald R. Miller,
Peter D. Reaven,
Julie A. Lynch,
Marijana Vujkovic,
Todd L. Edwards
Affiliations
Nikhil K. Khankari
Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 2525 West End Ave, Suite 700, Nashville, TN 37203, USA; 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.
Jacob M. Keaton
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
Venexia M. Walker
Medical Research Council, Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Bristol Medical School: Population Health Sciences, University of Bristol, Bristol, UK; Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Kyung Min Lee
VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA
Megan M. Shuey
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 2525 West End Ave, Suite 700, Nashville, TN 37203, USA
Shoa L. Clarke
Departments of Medicine and Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
Kent R. Heberer
VA Palo Alto Health Care System, Palo Alto, CA, USA; Departments of Medicine and Endocrinology, Stanford University School of Medicine, Stanford, CA, USA
Donald R. Miller
Center for Healthcare Organization and Implementation Research, Bedford VA Healthcare System, Bedford, MA, USA; Center for Population Health, Department of Biomedical and Nutritional Sciences, University of Massachusetts, Lowell, MA, USA
Peter D. Reaven
Phoenix VA Health Care Center, Phoenix, AZ, USA; College of Medicine, University of Arizona, Phoenix, AZ, USA
Julie A. Lynch
VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, USA; College of Nursing and Health Sciences, University of Massachusetts, Lowell, MA, USA
Marijana Vujkovic
Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
Todd L. Edwards
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, 2525 West End Ave, Suite 700, Nashville, TN 37203, USA; Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Nashville VA Medical Center, Nashville, TN, USA; Corresponding author at: Dr. Todd L. Edwards, Division of Epidemiology, Vanderbilt University Medical Center, 2525 West End Ave, Suite 600, Nashville, TN 37203, USA.
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.
