title: Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels.
abstract: OBJECTIVE
  Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that influences plasma low-density lipoprotein concentration and susceptibility to coronary heart disease. Circulating PCSK9 levels show considerable interindividual differences, but the factors responsible for this variation are largely unknown.
  
  
  RESULTS
  We analyzed circulating PCSK9 levels in 4 cohorts of healthy, middle-aged Swedes (n=5722) and found that PCSK9 levels varied over ≈50-fold range, showed a positive relationship with plasma low-density lipoprotein-cholesterol concentration, and were associated with plasma triglyceride, fibrinogen, insulin, and glucose concentrations. A genome-wide association study conducted in 2 cohorts (n=1215) failed to uncover common genetic variants robustly associated with variation in circulating PCSK9 level. As expected, the minor allele of the PCSK9 R46L variant was in all cohorts associated with reduced PCSK9 levels and decreased plasma low-density lipoprotein-cholesterol concentrations, but no relationship was observed with the plasma triglyceride concentration. Further mapping of the PCSK9 locus revealed a common polymorphism (rs2479415, minor allele frequency 43.9%), located ≈6 kb upstream from PCSK9, which is independently associated with increased circulating PCSK9 levels.
  
  
  CONCLUSIONS
  Common and low-frequency genetic variants in the PCSK9 locus influence the pronounced interindividual variation in circulating PCSK9 levels in healthy, middle-aged white (predominantly Swedish) subjects.
authors.affiliation: Cardiovascular Genetics and Genomics Group, Center for Molecular Medicine, L8:02, Karolinska University Hospital Solna, SE-17176 Stockholm, Sweden.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Chernogubova
authors.forename: Rona
authors.initials: R
authors.lastname: Strawbridge
authors.forename: Hovsep
authors.initials: H
authors.lastname: Mahdessian
authors.forename: Anders
authors.initials: A
authors.lastname: Mälarstig
authors.forename: Sergey
authors.initials: S
authors.lastname: Krapivner
authors.forename: Bruna
authors.initials: B
authors.lastname: Gigante
authors.forename: Mai-Lis
authors.initials: ML
authors.lastname: Hellénius
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Jason S
authors.initials: JS
authors.lastname: Troutt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Konrad
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Ferdinand M
authors.initials: FM
authors.lastname: van 't Hooft
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D015810:Linkage Disequilibrium; D008099:Liver / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D012697:Serine Endopeptidases / Q000097:blood* / Q000235:genetics*; D013548:Sweden; D014280:Triglycerides / Q000097:blood
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D008078:Cholesterol, LDL; D007328:Insulin; D012333:RNA, Messenger; D014280:Triglycerides; D005340:Fibrinogen; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases