Clinical Utility of Lipoprotein(a) and LPA Genetic Risk Score in Risk Prediction of Incident Atherosclerotic Cardiovascular Disease

Key Points

Question

Does measurement of lipoprotein(a) and/or LPA genetic risk score (GRS) have clinical utility in risk prediction of incident atherosclerotic cardiovascular disease (ASCVD)?

Findings

In this cohort of 283 540 adults recruited by the UK Biobank, both measured lipoprotein(a) and LPA GRS were associated with comparable risk of incident ASCVD events. The LPA GRS did not yield additional prognostic information beyond measured lipoprotein(a), and both measured lipoprotein(a) and LPA GRS yielded modest improvements in the discrimination of ASCVD risk relative to the Pooled Cohort Equations or QRISK3.

Meaning

Cardiovascular risk assessment with lipoprotein(a) may be achieved with either direct measurement or an LPA GRS.

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.

Abstract

This study investigates whether a genetic risk score comprising 43 variants at the LPA gene, which encodes apolipoprotein(a), has clinical utility in assessing atherosclerotic cardiovascular disease risk compared with and in addition to lipoprotein(a) measurement.