title: Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.
abstract: OBJECTIVE
  Plasma low-density lipoprotein cholesterol (LDL-C) has been associated with aortic stenosis in observational studies; however, randomized trials with cholesterol-lowering therapies in individuals with established valve disease have failed to demonstrate reduced disease progression.
  
  
  OBJECTIVE
  To evaluate whether genetic data are consistent with an association between LDL-C, high-density lipoprotein cholesterol (HDL-C), or triglycerides (TG) and aortic valve disease.
  
  
  METHODS
  Using a Mendelian randomization study design, we evaluated whether weighted genetic risk scores (GRSs), a measure of the genetic predisposition to elevations in plasma lipids, constructed using single-nucleotide polymorphisms identified in genome-wide association studies for plasma lipids, were associated with aortic valve disease. We included community-based cohorts participating in the CHARGE consortium (n = 6942), including the Framingham Heart Study (cohort inception to last follow-up: 1971-2013; n = 1295), Multi-Ethnic Study of Atherosclerosis (2000-2012; n = 2527), Age Gene/Environment Study-Reykjavik (2000-2012; n = 3120), and the Malmö Diet and Cancer Study (MDCS, 1991-2010; n = 28,461).
  
  
  METHODS
  Aortic valve calcium quantified by computed tomography in CHARGE and incident aortic stenosis in the MDCS.
  
  
  RESULTS
  The prevalence of aortic valve calcium across the 3 CHARGE cohorts was 32% (n = 2245). In the MDCS, over a median follow-up time of 16.1 years, aortic stenosis developed in 17 per 1000 participants (n = 473) and aortic valve replacement for aortic stenosis occurred in 7 per 1000 (n = 205). Plasma LDL-C, but not HDL-C or TG, was significantly associated with incident aortic stenosis (hazard ratio [HR] per mmol/L, 1.28; 95% CI, 1.04-1.57; P = .02; aortic stenosis incidence: 1.3% and 2.4% in lowest and highest LDL-C quartiles, respectively). The LDL-C GRS, but not HDL-C or TG GRS, was significantly associated with presence of aortic valve calcium in CHARGE (odds ratio [OR] per GRS increment, 1.38; 95% CI, 1.09-1.74; P = .007) and with incident aortic stenosis in MDCS (HR per GRS increment, 2.78; 95% CI, 1.22-6.37; P = .02; aortic stenosis incidence: 1.9% and 2.6% in lowest and highest GRS quartiles, respectively). In sensitivity analyses excluding variants weakly associated with HDL-C or TG, the LDL-C GRS remained associated with aortic valve calcium (P = .03) and aortic stenosis (P = .009). In instrumental variable analysis, LDL-C was associated with an increase in the risk of incident aortic stenosis (HR per mmol/L, 1.51; 95% CI, 1.07-2.14; P = .02).
  
  
  CONCLUSIONS
  Genetic predisposition to elevated LDL-C was associated with presence of aortic valve calcium and incidence of aortic stenosis, providing evidence supportive of a causal association between LDL-C and aortic valve disease. Whether earlier intervention to reduce LDL-C could prevent aortic valve disease merits further investigation.
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden2Department of Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden3Department of Clinical Sciences, Lund University, Malmö, Sweden4Program in Medical and Pop.
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.affiliation: McGill University Health Center, Preventive and Genomic Cardiology, Montreal, Quebec, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Luk
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Christina-Alexandra
authors.initials: CA
authors.lastname: Schulz
authors.affiliation: McGill University Health Center, Preventive and Genomic Cardiology, Montreal, Quebec, Canada6McGill University Health Center and Research Institute, Department of Medicine, Montreal, Quebec, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston.
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: George
authors.initials: G
authors.lastname: Hindy
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Gull
authors.initials: G
authors.lastname: Rukh
authors.affiliation: McGill University Health Center, Preventive and Genomic Cardiology, Montreal, Quebec, Canada.
authors.forename: Line
authors.initials: L
authors.lastname: Dufresne
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Department of Medicine, University of Washington, Seattle.
authors.forename: David S
authors.initials: DS
authors.lastname: Owens
authors.affiliation: National Institute on Aging, Bethesda, Maryland.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.affiliation: Department of Biostatistics, University of Washington, Seattle.
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Kerr
authors.affiliation: Department of Biostatistics, University of Washington, Seattle.
authors.forename: Quenna
authors.initials: Q
authors.lastname: Wong
authors.affiliation: Icelandic Heart Association Research Institute, Kopavogur, Iceland12Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA, Los Angeles, California.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Budoff
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA, Los Angeles, California.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts15Framingham Heart Study, Framingham, Massachusetts.
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: University of Virginia, Charlottesville.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rich
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts7Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston17Cardiology Division, Massachusetts General Hospi.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Icelandic Heart Association Research Institute, Kopavogur, Iceland12Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Framingham Heart Study, Framingham, Massachusetts17Cardiology Division, Massachusetts General Hospital, Boston18NHLBI Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Post
authors.affiliation: McGill University Health Center, Preventive and Genomic Cardiology, Montreal, Quebec, Canada6McGill University Health Center and Research Institute, Department of Medicine, Montreal, Quebec, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Thanassoulis
mesh_terms: D000368:Aged; D001021:Aortic Valve / Q000737:chemistry; D001024:Aortic Valve Stenosis / Q000453:epidemiology / Q000235:genetics*; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics; D000082882:Bicuspid Aortic Valve Disease; D002118:Calcium / Q000032:analysis*; D015984:Causality; D008078:Cholesterol, LDL / Q000097:blood* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006330:Heart Defects, Congenital / Q000453:epidemiology / Q000235:genetics*; D006349:Heart Valve Diseases / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
chemical_list: D008078:Cholesterol, LDL; D002118:Calcium