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

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 [b = -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: beta = 0.73 (SE = 0.33), P = 0.029, LLS offspring vs partners: beta = 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.