Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease-Free Survival, and Mortality Risk: A Mendelian Randomization Analysis.

This genetic association study uses mendelian randomization to examine the association between genetically determined lipoprotein(a) levels and the parental life span, chronic disease-free survival, and mortality risk of individuals with elevated levels. Importance 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. Objective 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. Design, Setting, and Participants 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 & x202f;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. Exposures Genetically determined and measured Lp(a) levels. Main Outcomes and Measures Parental life span, health span, and all-cause mortality. Results In 139 & x202f;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 x 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 x 10(-18)) and health span (-0.0019 [0.0003]; P = 3.00 x 10(-13)) was noted. In 18 & x202f;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 (beta coefficient [SE], 0.194 [0.064]). Conclusions and Relevance 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. Question Is long-term exposure to elevated lipoprotein(a) levels associated with shorter life span? Findings In this genetic association study including 139 & x202f;362 participants, 2-sample mendelian randomization showed that genetically elevated lipoprotein(a) levels were associated with parental life span. Measured lipoprotein(a) levels were also associated with all-cause mortality in a population-based study. Meaning Results of this study provide additional knowledge on the potential biological determinants of human longevity phenotypes and a rationale for trials of lipoprotein(a)-lowering therapy in individuals with high lipoprotein(a) levels.