title: LDL-c-linked SNPs are associated with LDL-c and myocardial infarction despite lipid-lowering therapy in patients with established vascular disease.
abstract: BACKGROUND
  Several single-nucleotide polymorphisms (SNPs) are associated with both plasma low-density lipoprotein cholesterol (LDL-c) level and coronary artery disease in the general population. It is unclear whether these associations also apply to patients with vascular disease and whether the associations are independent of lipid-lowering therapy.
  
  
  METHODS
  Single-nucleotide polymorphisms associated with plasma LDL-c and vascular risk in the general population (rs11206510 (PCSK9), rs1122608 (LDLR), rs579459 (ABO) and rs599839 (SORT1)) were genotyped in a prospective cohort study of 5482 patients with vascular disease. We determined the association between LDL-c-associated alleles and plasma LDL-c levels and the risk of new vascular events.
  
  
  RESULTS
  All tested SNPs were associated with LDL-c plasma levels with a magnitude between +0·06 (95% CI 0·02-0·10) mM and +0·14 (95% CI 0·09-0·18) mM per LDL-c-increasing allele. The associations were independent of the use of lipid-lowering medication, except for rs579459, for which the association was not present in patients using lipid-lowering medication. In patients with 7-8 risk alleles for these SNPs, 59% of the patients treated with lipid-lowering medication did not reach the LDL-c target of <2·5 mM compared with 45% in patients with 3 or fewer risk alleles. LDL-c-increasing alleles were not associated with increased risk of vascular events in patients not using lipid-lowering medication (HRs: 1·01; 95% CI: 0·93-1·09). In patients using lipid-lowering medication, the risk of myocardial infarction increased with 14% (HRs: 1·14; 95% CI: 1·01-1·28) per allele.
  
  
  CONCLUSIONS
  In patients with established vascular disease, the studied SNPs increase LDL-c plasma levels. LDL-c-increasing alleles may be associated with increased risk of myocardial infarction in patients treated with lipid-lowering medication, but not in patients not treated with lipid-lowering medication.
authors.affiliation: Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Anton P
authors.initials: AP
authors.lastname: van de Woestijne
authors.forename: Yolanda
authors.initials: Y
authors.lastname: van der Graaf
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: de Borst
authors.forename: Ale
authors.initials: A
authors.lastname: Algra
authors.forename: Wilko
authors.initials: W
authors.lastname: Spiering
authors.forename: Frank L J
authors.initials: FL
authors.lastname: Visseren
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics; D011446:Prospective Studies; D012697:Serine Endopeptidases / Q000235:genetics; D014652:Vascular Diseases / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: LDL-cholesterol; SNP; secondary prevention; statin