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

Iris Postmus; Joris Deelen; Sanaz Sedaghat; Stella Trompet; Anton Jm de Craen; Bastiaan T Heijmans; Oscar H Franco; Albert Hofman; Abbas Dehghan; P Eline Slagboom; Rudi Gj Westendorp; J Wouter Jukema

doi:10.1093/ije/dyv031

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

Iris Postmus, Joris Deelen, Sanaz Sedaghat, Stella Trompet, Anton Jm de Craen, Bastiaan T Heijmans, Oscar H Franco, Albert Hofman, Abbas Dehghan, P Eline Slagboom, Rudi Gj Westendorp, J Wouter Jukema

27 Citations (Scopus)

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 × 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). Conclusion: 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.

Original language	English
Journal	International Journal of Epidemiology
Volume	44
Issue number	2
Pages (from-to)	604-612
Number of pages	9
ISSN	0300-5771
DOIs	https://doi.org/10.1093/ije/dyv031
Publication status	Published - 27 May 2015

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@article{09890d51071041b4a7cad9cf4a4ca7bd,

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 × 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). Conclusion: 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.",

author = "Iris Postmus and Joris Deelen and Sanaz Sedaghat and Stella Trompet and {de Craen}, {Anton Jm} and Heijmans, {Bastiaan T} and Franco, {Oscar H} and Albert Hofman and Abbas Dehghan and Slagboom, {P Eline} and Westendorp, {Rudi Gj} and Jukema, {J Wouter}",

year = "2015",

month = may,

day = "27",

doi = "10.1093/ije/dyv031",

language = "English",

volume = "44",

pages = "604--612",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "2",

}

TY - JOUR

T1 - LDL cholesterol still a problem in old age?

T2 - A Mendelian randomization study

AU - Postmus, Iris

AU - Deelen, Joris

AU - Sedaghat, Sanaz

AU - Trompet, Stella

AU - de Craen, Anton Jm

AU - Heijmans, Bastiaan T

AU - Franco, Oscar H

AU - Hofman, Albert

AU - Dehghan, Abbas

AU - Slagboom, P Eline

AU - Westendorp, Rudi Gj

AU - Jukema, J Wouter

PY - 2015/5/27

Y1 - 2015/5/27

N2 - 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 × 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). Conclusion: 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.

AB - 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 × 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). Conclusion: 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.

U2 - 10.1093/ije/dyv031

DO - 10.1093/ije/dyv031

M3 - Journal article

C2 - 25855712

SN - 0300-5771

VL - 44

SP - 604

EP - 612

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 2

ER -

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

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