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LDL cholesterol still a problem in old age? A Mendelian randomization study.

Iris Postmus1, Joris Deelen1, Sanaz Sedaghat2

  • 1Department 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.

International Journal of Epidemiology
|April 10, 2015
PubMed
Summary

Genetic predisposition to high LDL-C increases mortality risk throughout life, even in the oldest individuals. A favorable LDL genetic risk profile is linked to longer lifespans and familial longevity.

Keywords:
LDL-cholesterolMendelian randomizationgenetic risk scoreold age

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Area of Science:

  • Genetics
  • Cardiovascular Health
  • Gerontology

Background:

  • Observational studies in older adults show inconsistent links between cholesterol and mortality.
  • Reverse causality may underestimate low-density lipoprotein cholesterol (LDL-C) risks in the elderly.
  • Genetic risk scores (GRS) offer a method to assess lifetime LDL-C exposure, overcoming reverse causality issues.

Purpose of the Study:

  • To investigate the association between LDL genetic risk score (GRS) and mortality in older populations.
  • To determine if LDL GRS can predict lifetime LDL-C levels and mortality risk, independent of reverse causality.
  • To explore the relationship between LDL GRS and familial longevity.

Main Methods:

  • A weighted LDL GRS was developed using 51 single nucleotide polymorphisms associated with LDL-C.
  • The LDL GRS was calculated in three Dutch cohorts: Leiden Longevity Study (LLS), Leiden 85-plus study, and Rotterdam Study.
  • Associations between LDL GRS, LDL-C levels, age, familial longevity, and mortality were assessed.

Main Results:

  • Higher LDL GRS correlated with higher LDL-C levels up to age 90.
  • The frequency of LDL-increasing alleles decreased with age.
  • Individuals with a genetic predisposition for longevity had lower LDL GRS.
  • High LDL GRS was associated with increased all-cause mortality in those over 90 years.

Conclusions:

  • A genetic predisposition to high LDL-C contributes to mortality across the lifespan, including in advanced age.
  • A beneficial LDL genetic risk profile is associated with familial longevity.
  • LDL GRS is a valuable tool for assessing long-term cardiovascular risk and its impact on longevity.