Genetics
Measured Lp(a) and a 43-variant genetic risk score predict cardiovascular disease equally well, but adding either only modestly improves standard risk scores, in 374,099 UK Biobank participants (JAMA Cardiol 2021)
Original title: Clinical Utility of Lipoprotein(a) and LPA Genetic Risk Score in Risk Prediction of Incident Atherosclerotic Cardiovascular Disease
In the UK Biobank, the authors compared measured Lp(a) with an LPA genetic risk score (GRS, 43 variants) in 374,099 unrelated individuals with both genotype and Lp(a) data, part of a cohort of approximately 500,000 volunteers followed a median 11.1 years, during which 15,444 (5.1%) developed incident atherosclerotic cardiovascular disease. The LPA GRS explained about 60% of the variation in measured Lp(a) among White/European individuals. Both measured Lp(a) (HR per 120 nmol/L increase 1.26, 95% CI 1.23-1.28) and the LPA GRS (HR 1.29, 95% CI 1.26-1.33) were independently associated with incident disease (both P<.001), though the GRS association was substantially attenuated after adjusting for measured Lp(a). Adding either measured Lp(a) or the LPA GRS to the QRISK3 score provided only modest improvement in risk discrimination (AUC 0.640 vs 0.642, P=.005 and P=.01 respectively). The findings suggest either direct Lp(a) measurement or a genetic risk score can inform cardiovascular risk assessment at middle age, with measured Lp(a) capturing most of the relevant genetic signal.
Original abstract
Importance: Lipoprotein(a) is a highly heritable biomarker independently associated with atherosclerotic cardiovascular disease (ASCVD). It is unclear whether measured lipoprotein(a) or genetic factors associated with lipoprotein(a) can provide comparable or additional prognostic information for primary prevention.
Objective: To determine whether a genetic risk score (GRS) comprising 43 variants at the LPA gene, which encodes apolipoprotein(a), has clinical utility in assessing ASCVD risk compared with and in addition to lipoprotein(a) measurement.
Design, Setting, And Participants: The UK Biobank is a prospective observational study of approximately 500 000 volunteers aged 40 to 69 years who were recruited from 22 sites across the United Kingdom between 2006 and 2010. Using externally derived weights, an LPA GRS was calculated for 374 099 unrelated individuals with array-derived genotypes and lipoprotein(a) measures. Data were analyzed from April 2020 to March 2020.
Exposures: Measured lipoprotein(a) and LPA GRS.
Main Outcomes And Measures: We estimated the associations between measured lipoprotein(a) and LPA GRS with the incidence of ASCVD (peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) using Cox proportional hazards models. To determine the utility of using measured lipoprotein(a) and LPA GRS as risk enhancers for ASCVD, we assessed the potential improvement in ASCVD risk discrimination by QRISK3 and Pooled Cohort Equations among individuals with borderline to intermediate risk (n = 113 703 and 144 350, respectively).
Results: The mean age of the overall study population was 57.6 years, and 204 355 individuals were female (54.6%). During a median follow-up of 11.1 years (interquartile range, 1.4 years), 15 444 individuals developed an incident ASCVD event (5.1%). The LPA GRS explained approximately 60% of the variation in measured lipoprotein(a) for White/European individuals. Independently, both lipoprotein(a) and LPA GRS were associated with incident, composite ASCVD (hazard ratio per 120 nmol/L increase, 1.26; 95% CI, 1.23-1.28 vs hazard ratio, 1.29; 95% CI, 1.26-1.33; P < .001). The association between LPA GRS and ASCVD was substantially attenuated after adjusting for measured lipoprotein(a). Adding measured lipoprotein(a) or LPA GRS to QRISK3 provided modest improvements to the risk discrimination of incident ASCVD events (area under the receiver operating curve, 0.640; 95% CI, 0.633-0.647 vs 0.642; 95% CI, 0.635-0.649 for both; P = .005 and P = .01, respectively).
Conclusions And Relevance: When indicated, cardiovascular risk assessment with lipoprotein(a) at middle-age may include direct measurement or an LPA GRS.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.