title: LDL cholesterol still a problem in old age? A Mendelian randomization study.
abstract: BACKGROUND
  Observational studies in older subjects have shown no or inverse associations between cholesterol levels and mortality. However, in old age plasma low-density lipoprotein cholesterol (LDL-C) may not reflect the lifetime level due to reverse causality, and hence the risk may be underestimated. In the current study, we used an LDL genetic risk score (GRS) to overcome this problem.
  
  
  METHODS
  A weighted GRS was created using 51 single nucleotide polymorphisms associated with LDL-C levels. The LDL GRS was calculated in three Dutch cohorts: the Leiden Longevity Study (LLS) (n = 3270), the Leiden 85-plus study (n = 316) and the Rotterdam Study (n = 4035). We assessed the association between the LDL GRS and LDL-C levels, chronological age, familial longevity and mortality.
  
  
  RESULTS
  Up to 90 years of age, in each age stratum individuals with high LDL GRS had higher LDL-C levels (P = 0.010 to P = 1.1 x 10(-16)). The frequency of LDL-increasing alleles decreased with increasing age [β = -0.021 (SE = 0.01) per year, P = 0.018]. Moreover, individuals with a genetic predisposition for longevity had significantly lower LDL GRS compared with age-matched individuals of the general population [LLS nonagenarians vs > 90 years: β = 0.73 (SE = 0.33), P = 0.029, LLS offspring vs partners: β = 0.66 (SE = 0.23), P = 0.005]. In longitudinal analysis, high GRS was associated with increased all-cause mortality in individuals > 90 years, with a 13% increased risk in individuals with the highest LDL GRS (P-trend = 0.043).
  
  
  CONCLUSIONS
  Results of the current study indicate that a genetic predisposition to high LDL-C levels contributes to mortality throughout life, including in the oldest old, and a beneficial LDL genetic risk profile is associated with familial longevity.
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Iris
authors: I
authors: Postmus
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Joris
authors: J
authors: Deelen
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Sanaz
authors: S
authors: Sedaghat
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyd
authors: Stella
authors: S
authors: Trompet
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Anton J M
authors: AJ
authors: de Craen
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Bastiaan T
authors: BT
authors: Heijmans
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Oscar H
authors: OH
authors: Franco
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: Abbas
authors: A
authors: Dehghan
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
authors: P Eline
authors: PE
authors: Slagboom
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyd
authors: Rudi G J
authors: RG
authors: Westendorp
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyden Academy of Vitality and Ageing, Leiden, The Netherlands, Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark, Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands, Leyd
authors: J Wouter
authors: JW
authors: Jukema
mesh_terms: D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality; D008078:Cholesterol, LDL / Q000235:genetics* / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000401:mortality; D008136:Longevity / Q000235:genetics; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D008078:Cholesterol, LDL
keywords: LDL-cholesterol; Mendelian randomization; genetic risk score; old age