Highlight
This large registry-based cohort study reveals that first-degree relatives (FDRs) of individuals with elevated lipoprotein(a) [Lp(a)] levels have a significantly increased incidence of major adverse cardiovascular events (MACE). Cascade screening within families could enable earlier identification of high-risk individuals for targeted cardiovascular prevention.
Study Background
Lipoprotein(a) is a genetically determined lipoprotein variant recognized as a causal risk factor in the development of atherosclerotic cardiovascular disease (ASCVD). Elevated Lp(a) promotes proatherogenic, prothrombotic, and proinflammatory processes that accelerate vascular disease, independently of traditional lipid measures such as LDL cholesterol. Despite its strong heritability and documented impact on cardiovascular risk, the role of family history of elevated Lp(a) in predicting risk among first-degree relatives has remained less defined.
Cardiovascular disease remains the leading cause of morbidity and mortality globally, with early identification of high-risk individuals being critical for optimized prevention strategies. Targeted cascade screening based on familial hyperlipoproteinemia or elevated biomarkers could offer a precision medicine approach, but robust epidemiological evidence on relative risk in relatives based on index Lp(a) status has been lacking.
Study Design
This study leveraged the Swedish STRIREG registry to perform a retrospective cohort analysis. The index cohort consisted of 41,304 individuals with routine plasma Lp(a) measurements. First-degree relatives aged 35 to 69 years (n=61,715), without their own Lp(a) measurements, were identified. The FDRs were grouped based on the Lp(a) percentile of the index individual into four strata: below 50th percentile, 50th to less than 80th percentile, 80th to less than 95th percentile, and 95th percentile or higher.
The primary outcome was major adverse cardiovascular events (MACE), encompassing cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization. Competing risk-adjusted cumulative incidence analyses and Cox proportional hazards modelling were conducted to determine the association between index Lp(a) strata and MACE incidence in relatives. Additionally, a nested subanalysis examined concordance of plasma Lp(a) levels among paired index-FDR dyads with measured values.
Key Findings
During a prolonged median follow-up of 19 years (interquartile range 11-26 years), 2043 major cardiovascular events occurred in first-degree relatives. Cumulative incidence of MACE by age 65 increased progressively with the index individual’s Lp(a) stratum: 6.2% (<50th percentile), 7.0% (50th-<80th), 7.5% (80th-<95th), and 8.1% (≥95th), with a statistically significant trend (P < .001).
Hazard ratios (HRs) for MACE compared to FDRs of indexes below the 50th percentile were: 1.08 (95% CI: 0.97-1.19) for the 50th-<80th percentile group, 1.30 (1.15-1.47) for the 80th-<95th percentile group, and 1.28 (1.06-1.55) for those with index values ≥95th percentile (Ptrend < .001). These findings indicate about a 28-30% increased relative risk of MACE in relatives of individuals with elevated Lp(a) at or above the 80th percentile.
In the nested concordance analysis of 4243 index-relative pairs where both had measured Lp(a), 86% of pairs with index Lp(a) below the 80th percentile also had FDR Lp(a) below this threshold. The concordance decreased to 53% for pairs with index Lp(a) ≥80th percentile, consistent with the known genetic yet complex inheritance pattern of Lp(a).
Expert Commentary
This study provides compelling epidemiological evidence linking elevated Lp(a) in index patients to increased cardiovascular risk in their first-degree relatives. The long follow-up, large sample size, and robust statistical methodology strengthen the conclusions.
Importantly, the graded risk increase with higher index Lp(a) strata aligns with biological plausibility that genetically determined elevations of Lp(a) propagate increased ASCVD risk within families. The slightly lower concordance of elevated Lp(a>80th percentile) among relatives likely reflects genetic variability and incomplete penetrance.
These data support current guideline statements from the European Atherosclerosis Society advocating measurement of Lp(a) once in life and consideration of cascade screening in relatives of individuals with very high Lp(a). Early identification of elevated Lp(a) could prompt intensified lipid-lowering therapy and other preventive measures.
Limitations include lack of direct Lp(a) measurements in most relatives, reliance on registry data for clinical endpoints, and potential confounding by unmeasured familial environmental factors. Nonetheless, the findings are generalizable to populations with similar genetic backgrounds and healthcare infrastructure.
Conclusion
This registry-based cohort study robustly demonstrates that first-degree relatives of individuals with elevated plasma Lp(a) are at significantly higher risk of major cardiovascular events. These results underscore the potential clinical utility of cascade screening strategies to identify high-risk relatives who may benefit from early preventive interventions targeting Lp(a) and broader cardiovascular risk factors. Future research should explore integrated risk prediction tools incorporating familial Lp(a) status and evaluate the impact of targeted Lp(a)-lowering therapies in this high-risk group.
Funding and ClinicalTrials.gov
No specific funding or clinical trial registration was reported for this observational registry study.
References
- Kindborg G, Eriksson Hogling D, Häbel H, et al. Major cardiovascular events in first-degree relatives of individuals with elevated plasma lipoprotein(a): a registry-based cohort study. Eur Heart J. 2026;47(26):3390-3400. doi:10.1093/eurheartj/ehac123
- Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412-423.
- Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844-2853.
- European Atherosclerosis Society Consensus Panel. Lipoprotein(a): Evidence, risk, and emerging therapies (Consensus Statement). Eur Heart J. 2020;41(39):3929-3943.
