title: A genetic risk score is significantly associated with statin therapy response in the elderly population.
abstract: The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: D M
authors.initials: DM
authors.lastname: Ciuculete
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Bandstein
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Benedict
authors.affiliation: Department of Internal Medicine, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Waeber
authors.affiliation: Department of Internal Medicine, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: Department of Medicine, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: H B
authors.initials: HB
authors.lastname: Schiöth
authors.affiliation: Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Mwinyi
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics*; D001786:Blood Glucose; D015820:Cadherins / Q000235:genetics; D008078:Cholesterol, LDL / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010599:Pharmacokinetics; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001057:Apolipoproteins E; D001786:Blood Glucose; D015820:Cadherins; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010750:Phosphoproteins; D000099183:Sortilin; C000715087:ABCC2 protein, human; C454220:CELSR1 cadherin, human; C485740:PSRC1 protein, human
keywords: pharmacogenetics; polygenetic risk score; random forest analysis; single nucleotide polymorphism; statins