title: Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population.
abstract: OBJECTIVE
  The purpose of this study was to determine whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeat polymorphism) prospectively associate with increased risk of aortic valve stenosis (AVS).
  
  
  BACKGROUND
  The etiologic basis of AVS is unclear. Recent data implicate an LPA genetic variant (rs10455872), associated with Lp(a) levels, in calcific AVS.
  
  
  METHODS
  We combined data from 2 prospective general population studies, the Copenhagen City Heart Study (1991 to 2011; n = 10,803) and the Copenhagen General Population Study (2003 to 2011; n = 66,877), following up 77,680 Danish participants for as long as 20 years, during which time 454 were diagnosed with AVS. We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design.
  
  
  RESULTS
  Elevated Lp(a) levels were associated with multivariable adjusted hazard ratios for AVS of 1.2 (95% confidence interval [CI]: 0.8 to 1.7) for 22nd to 66th percentile levels (5 to 19 mg/dl), 1.6 (95% CI: 1.1 to 2.4) for 67th to 89th percentile levels (20 to 64 mg/dl), 2.0 (95% CI: 1.2 to 3.4) for 90th to 95th percentile levels (65 to 90 mg/dl), and 2.9 (95% CI: 1.8 to 4.9) for levels greater than 95th percentile (>90 mg/dl), versus levels less than the 22nd percentile (<5 mg/dl; trend, p < 0.001). Lp(a) levels were elevated among carriers of rs10455872 and rs3798220 minor alleles, and of low number of KIV-2 repeats (trend, all p < 0.001). Combining all genotypes, instrumental variable analysis yielded a genetic relative risk for AVS of 1.6 (95% CI: 1.2 to 2.1) for a 10-fold Lp(a) increase, comparable to the observational hazard ratio of 1.4 (95% CI: 1.2 to 1.7) for a 10-fold increase in Lp(a) plasma levels.
  
  
  CONCLUSIONS
  Elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS in the general population, with levels >90 mg/dl predicting a threefold increased risk.
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Pia R
authors.initials: PR
authors.lastname: Kamstrup
authors.affiliation: Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: Boerge.Nordestgaard@regionh.dk.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000097:blood* / Q000453:epidemiology / Q000209:etiology; D015415:Biomarkers / Q000097:blood; D003718:Denmark / Q000453:epidemiology; D005260:Female; D006801:Humans; D006951:Hyperlipoproteinemias / Q000097:blood* / Q000150:complications / Q000453:epidemiology; D015994:Incidence; D017270:Lipoprotein(a) / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance; D015995:Prevalence; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D017270:Lipoprotein(a)
keywords: AVS; CI; ICD; International Classification of Diseases; KIV-2; Lp(a); SNP; aortic valve stenosis; confidence interval; genes; kringle IV type 2; single nucleotide polymorphism