title: Robust association of the LPA locus with low-density lipoprotein cholesterol lowering response to statin treatment in a meta-analysis of 30 467 individuals from both randomized control trials and observational studies and association with coronary artery disease outcome during statin treatment.
abstract: OBJECTIVE
  The LPA single-nucleotide polymorphism rs10455872 has been associated with low-density lipoprotein cholesterol (LDLc) lowering response to statins in several randomized control trials (RCTs) and is a known coronary artery disease (CAD) marker. However, it is unclear what residual risk of CAD this marker may have during statin treatment.
  
  
  METHODS
  Using electronic medical records linked to the GoDARTS genotyped population, we identified over 8000 patients on statins in Tayside, Scotland.
  
  
  RESULTS
  We replicated the findings of the RCTs, with the G allele of rs10455872 being associated with a 0.10 mmol/l per allele poorer reduction in LDLc in response to statin treatment, and conducted a meta-analysis with previously published RCTs (P = 1.46 × 10, n = 30 467). We showed an association between rs10455872 and CAD in statin-treated individuals and have replicated this finding in the Utrecht Cardiovascular Pharmacogenetics study (combined odds ratio 1.41, 95% confidence interval 1.17-1.68, P = 4.5 × 10, n = 8822) suggesting that statin treatment does not abrogate this well-established genetic risk for CAD. Furthermore, in a Cox proportional hazards model with LDLc measured time dependently, we demonstrated that the relationship between CAD and rs10455872 was independent of LDLc during statin treatment.
  
  
  CONCLUSIONS
  Individuals with the G allele of rs10455872, which represents approximately one in seven patients, have a higher risk of CAD than the majority of the population even after treatment with statins; and therefore represent a vulnerable group requiring an alternative medication in addition to statin treatment.
authors.affiliation: aMedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee bWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK cDivision of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University dDepartment of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Donnelly
authors.forename: Natalie R
authors.initials: NR
authors.lastname: van Zuydam
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhou
authors.forename: Roger
authors.initials: R
authors.lastname: Tavendale
authors.forename: Fiona
authors.initials: F
authors.lastname: Carr
authors.forename: Anke H
authors.initials: AH
authors.lastname: Maitland-van der Zee
authors.forename: Maarten
authors.initials: M
authors.lastname: Leusink
authors.forename: Anthonius
authors.initials: A
authors.lastname: de Boer
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.forename: Alex S F
authors.initials: AS
authors.lastname: Doney
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics* / Q000517:prevention & control*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D016014:Linear Models; D017270:Lipoprotein(a) / Q000235:genetics*; D008297:Male; D064887:Observational Studies as Topic; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D012606:Scotland
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017270:Lipoprotein(a)
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