title: Elevated Lipoprotein(a) Levels, LPA Risk Genotypes, and Increased Risk of Heart Failure in the General Population.
abstract: OBJECTIVE
  This study sough to test whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (low number of kringle IV type 2 repeats, rs3798220 and rs10455872, minor allele carriers) are associated with an increased risk of heart failure (HF).
  
  
  BACKGROUND
  Elevated lipoprotein(a) levels represent a genetically determined risk factor for myocardial infarction (MI) and aortic valve stenosis (AVS). It is presently unknown whether elevated lipoprotein(a) levels also cause heart failure (HF).
  
  
  METHODS
  We combined 2 general population studies, the Copenhagen City Heart Study (n = 10,855) and the Copenhagen General Population Study (n = 87,242), which totaled 98,097 Danish participants, of whom 4,122 were diagnosed with HF (1976 to 2013). We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design, assessing evidence of causality, and we performed mediation analyses.
  
  
  RESULTS
  Elevated lipoprotein(a) levels were associated with multivariable adjusted hazard ratios for HF of 1.10 (95% CI: 0.97 to 1.25) for the 34th to 66th percentiles (8 to 19 mg/dl), 1.24 (95% CI: 1.08 to 1.42) for the 67th to 90th percentiles (20 to 67 mg/dl), 1.57 (95% CI: 1.32 to 1.87) for the 91st to 99th percentiles (68 to 153 mg/dl), and 1.79 (95% CI: 1.18 to 2.73) for levels >99th percentile (>153 mg/dl) versus levels <34th percentile (<8 mg/dl) (trend, p < 0.001), corresponding to a population-attributable risk of 9%. By combining all LPA risk genotypes, instrumental variable analysis yielded a genetic relative risk for HF of 1.18 (95% CI: 1.04 to 1.34) per 10-fold higher lipoprotein(a) levels, which was comparable to the corresponding observational hazard ratio of 1.22 (95% CI: 1.11 to 1.35). Upon exclusion of participants diagnosed with MI or AVS, risk estimates were attenuated. Accordingly, 63% (95% CI: 45% to 99%) of HF risk was mediated via MI and AVS combined.
  
  
  CONCLUSIONS
  Elevated lipoprotein(a) levels and corresponding LPA risk genotypes were associated with an increased risk of HF consistent with a causal association. The association appeared to be partly mediated by MI and AVS.
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: pia.roerbaek.kamstrup@regionh.dk.
authors.forename: Pia R
authors.initials: PR
authors.lastname: Kamstrup
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
mesh_terms: D000368:Aged; D001024:Aortic Valve Stenosis / Q000453:epidemiology / Q000235:genetics; D003718:Denmark / Q000453:epidemiology; D005091:Exons; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D018082:Kringles / Q000235:genetics*; D017270:Lipoprotein(a) / Q000235:genetics / Q000378:metabolism*; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D017270:Lipoprotein(a)
keywords: genetics; heart failure; lipoproteins