Abstract
Elevated lipoprotein(a) (Lp[a]) levels are associated with atherosclerotic cardiovascular diseases. The association between high Lp(a) levels and human longevity phenotypes is, however, controversial. To examine whether genetically determined Lp(a) levels are associated with parental life span and chronic disease-free survival (health span) and the association between Lp(a) levels and long-term, all-cause mortality risk. In this genetic association study, cross-sectional mendelian randomization (UK Biobank [2006-2010] and LifeGen Consortium) and prospective analyses (European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk [1993-1997, with patients followed up to 2016]) were conducted using individual-level data on 139 362 participants. The association between a weighted genetic risk score of 26 independent single-nucleotide polymorphisms at the LPA locus on parental life span using individual participant data from the UK Biobank, as well as with summary statistics of a genome-wide association study of more than 1 million life spans (UK Biobank and LifeGen), were examined. The association between these single-nucleotide polymorphisms and the age at the end of the health span was tested using summary statistics of a previous genome-wide association study in the UK Biobank. The association between Lp(a) levels and all-cause mortality in the EPIC-Norfolk study was also investigated. Data were analyzed from December 2018 to December 2019. Genetically determined and measured Lp(a) levels. Parental life span, health span, and all-cause mortality. In 139 362 white British participants (mean [SD] age, 62.8 [3.9] years; 52% women) from the UK Biobank, increases in the genetic risk score (weighted for a 50-mg/dL increase in Lp[a] levels) were inversely associated with a high parental life span (odds ratio, 0.92; 95% CI, 0.89-0.94; P = 2.7 × 10-8). Using the Egger-mendelian randomization method, a negative association between LPA single-nucleotide polymorphisms and parental life span (mean [SD] Egger-mendelian randomization slope, -0.0019 [0.0002]; P = 2.22 × 10-18) and health span (-0.0019 [0.0003]; P = 3.00 × 10-13) was noted. In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064]). The results of this study suggest a potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality. The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels.
Highlights
Lipoprotein(a) (Lp[a]) consists of a low-density lipoprotein attached to apolipoprotein(a) by a disulfide bond
A recently published study by Langsted et al[8] revealed an association between high Lp(a) levels and cardiovascular and all-cause mortality in the general Danish population. This association could be owing to the fact that individuals with high Lp(a) levels are typically characterized by a smaller apolipoprotein(a) isoform size
Of the 139 362 UK Biobank participants included in this analysis, 17 686 were considered as having high parental life span, and 2932 individuals were defined as having 1 parent with exceptional longevity
Summary
Lipoprotein(a) (Lp[a]) consists of a low-density lipoprotein attached to apolipoprotein(a) by a disulfide bond. Plasma levels of Lp(a) are associated with a higher risk of a broad range of atherosclerotic cardiovascular disease (CVD).[1,2,3,4,5] The evidence linking Lp(a) levels and Lp(a)-raising genetic variants with all-cause mortality is not as consistent. A 1998 study of healthy centenarian individuals initiated a debate about the potential association between Lp(a) and longevity following the report that up to one-quarter of that population had high Lp(a) levels in the absence of any atherosclerotic CVD.[6] Another study of patients with documented coronary heart disease found no evidence of an association between high Lp(a) levels and all-cause mortality.[7] A recently published study by Langsted et al[8] revealed an association between high Lp(a) levels and cardiovascular and all-cause mortality in the general Danish population. This association could be owing to the fact that individuals with high Lp(a) levels are typically characterized by a smaller apolipoprotein(a) isoform size
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
