TY - JOUR
T1 - LDL cholesterol still a problem in old age? A Mendelian randomization study
AU - Postmus, Iris
AU - Deelen, Joris
AU - Sedaghat, Sanaz
AU - Trompet, Stella
AU - De Craen, Anton J.M.
AU - Heijmans, Bastiaan T.
AU - Franco, Oscar H.
AU - Hofman, Albert
AU - Dehghan, Abbas
AU - Slagboom, P. Eline
AU - Westendorp, Rudi G.J.
AU - Jukema, J. Wouter
N1 - Publisher Copyright:
© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
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.
KW - Genetic risk score
KW - LDL-cholesterol
KW - Mendelian randomization
KW - Old age
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U2 - 10.1093/ije/dyv031
DO - 10.1093/ije/dyv031
M3 - Article
C2 - 25855712
AN - SCOPUS:84936745278
SN - 0300-5771
VL - 44
SP - 604
EP - 612
JO - International journal of epidemiology
JF - International journal of epidemiology
IS - 2
ER -