title: Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI.
abstract: Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p<0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance.
authors: Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors: Bas J M
authors: BJ
authors: Peters
authors: Helmi
authors: H
authors: Pett
authors: Olaf H
authors: OH
authors: Klungel
authors: Bruno H Ch
authors: BH
authors: Stricker
authors: Bruce M
authors: BM
authors: Psaty
authors: Nicole L
authors: NL
authors: Glazer
authors: Kerri L
authors: KL
authors: Wiggins
authors: Josh C
authors: JC
authors: Bis
authors: Anthonius
authors: A
authors: de Boer
authors: Anke-Hilse
authors: AH
authors: Maitland-van der Zee
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008049:Lipase / Q000235:genetics; D008074:Lipoproteins / Q000235:genetics; D016015:Logistic Models; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D009426:Netherlands; D016017:Odds Ratio; D047495:PPAR gamma / Q000235:genetics; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D051122:Scavenger Receptors, Class B / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D002785:Sterol O-Acyltransferase / Q000235:genetics; D016896:Treatment Outcome
chemical_list: C416945:ABCG5 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C504173:LIPC protein, human; C475476:LRP1 protein, human; D008074:Lipoproteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D047495:PPAR gamma; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; C493492:sterol O-acyltransferase 1; D008049:Lipase; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases