title: Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk.
abstract: Therapeutic interventions that lower LDL-cholesterol effectively reduce the risk of coronary artery disease (CAD). However, statins, the most widely prescribed LDL-cholesterol lowering drugs, increase diabetes risk. We used genome-wide association study (GWAS) data in the public domain to investigate the relationship of LDL-C and diabetes and identify loci encoding potential drug targets for LDL-cholesterol modification without causing dysglycemia. We obtained summary-level GWAS data for LDL-C from GLGC, glycemic traits from MAGIC, diabetes from DIAGRAM and CAD from CARDIoGRAMplusC4D consortia. Mendelian randomization analyses identified a one standard deviation (SD) increase in LDL-C caused an increased risk of CAD (odds ratio [OR] 1.63 (95 % confidence interval [CI] 1.55, 1.71), which was not influenced by removing SNPs associated with diabetes. LDL-C/CAD-associated SNPs showed consistent effect directions (binomial P = 6.85 × 10(-5)). Conversely, a 1-SD increase in LDL-C was causally protective of diabetes (OR 0.86; 95 % CI 0.81, 0.91), however LDL-cholesterol/diabetes-associated SNPs did not show consistent effect directions (binomial P = 0.15). HMGCR, our positive control, associated with LDL-C, CAD and a glycemic composite (derived from GWAS meta-analysis of four glycemic traits and diabetes). In contrast, PCSK9, APOB, LPA, CETP, PLG, NPC1L1 and ALDH2 were identified as "druggable" loci that alter LDL-C and risk of CAD without displaying associations with dysglycemia. In conclusion, LDL-C increases the risk of CAD and the relationship is independent of any association of LDL-C with diabetes. Loci that encode targets of emerging LDL-C lowering drugs do not associate with dysglycemia, and this provides provisional evidence that new LDL-C lowering drugs (such as PCSK9 inhibitors) may not influence risk of diabetes.
authors.affiliation: Department of Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Tragante
authors.affiliation: Department of Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands. f.w.asselbergs@umcutrecht.nl.|Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK. f.w.asselbergs@umcutrecht.nl.|Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands. f.w.asselbergs@umcutrecht.nl.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Institute of Cardiovascular Science, University College London, 222 Euston Road, London, NW1 2DA, UK.|Department of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Swerdlow
authors.affiliation: Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.affiliation: Department of Biostatistics and Epidemiology, Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, 19104-6021, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul I W
authors.initials: PIW
authors.lastname: de Bakker
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA.|Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA. michael.holmes@ndph.ox.ac.uk.|Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA. michael.holmes@ndph.ox.ac.uk.|Clinical Trials Services Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Richard Doll Building, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK. michael.holmes@ndph.ox.ac.uk.
authors.forename: Michael V
authors.identifier: http://orcid.org/0000-0001-6617-0879
authors.initials: MV
authors.lastname: Holmes
mesh_terms: D015415:Biomarkers / Q000032:analysis*; D001786:Blood Glucose / Q000032:analysis; D008078:Cholesterol, LDL / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics* / Q000517:prevention & control; D055106:Genome-Wide Association Study; D005838:Genotype; D038321:Glycemic Index / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids / Q000737:chemistry*; D057182:Mendelian Randomization Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids