Genetically determined lipoprotein(a), or Lp(a), variations were correlated with overall and healthy lifespan in ways that suggest it has a causal impact, researchers reported.
An LPA gene sequence that would confer a 50-mg/dL higher Lp(a) level was linked to significant 8% to 9% lower likelihood of a long-lived parent (father 90+ or mother 93+) and 10% lower chance that one's parent had "exceptional longevity" (top 1% survival).
Duration of life free from chronic disease was also 8% to 9% lower for the same degree of genetic risk, Benoit Arsenault, PhD, of Université Laval in Quebec City, Quebec, and colleagues .
The mortality risk for individuals with Lp(a) levels in the top fifth percentiles was equivalent to being 1.5 years older in chronologic age.
The researchers pointed to a "potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality" in their study.
"The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels," the team wrote. "Only a long-term clinical trial of Lp(a)-level lowering with investigative therapies will inform on the clinical benefits of change in risk or health trajectories of individuals with high Lp(a) levels."
Lp(a)-lowering therapies are in development, with positive results in mid-stage trials with antisense agent AKCEA-APO(a)-Lrx. Its pivotal phase III in patients with established cardiovascular disease and Lp(a) ≥70 mg/dL is underway and anticipated to finish in April 2024.
The study included cross-sectional mendelian randomization data from the UK Biobank and LifeGen Consortium and prospective analyses from the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk with individual-level data on 139,362 participants.
The study included 8,976 participants with a long-lived father and 10,137 with a long-lived mother, as well as 2,932 with a parent in the top 1% for lifespan.
However, the samples included only individuals of European ancestry and the EPIC-Norfolk data was from a primary prevention setting "not optimal to inform a randomized clinical trial design, which will likely be conducted in secondary prevention settings," the group added.
Disclosures
The EPIC-Norfolk Study is funded by Cancer Research UK and the Medical Research Council.
Arsenault reported receiving grants from Ionis Pharmaceuticals and Pfizer and personal fees from Novartis.
Primary Source
JAMA Network Open
Arsenault BJ, et al "Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease–Free Survival, and Mortality Risk" JAMA Netw Open 2020; 3(2): e200129.