Abstract
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. 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. 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. Measured lipoprotein(a) and LPA GRS. 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). 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). When indicated, cardiovascular risk assessment with lipoprotein(a) at middle-age may include direct measurement or an LPA GRS.
Highlights
The distributions of measured lipoprotein(a), LPA genetic risk score (GRS), and the residual of measured vs LPA GRS-expected lipoprotein(a) for these individuals are shown across strata of ethnicity in eFigures 1 and 2 in the Supplement
A 120-nmol/L increase in measured lipoprotein(a) was significantly associated with increased risk of incident, composite atherosclerotic cardiovascular disease (ASCVD) events for White/European individuals, South Asian individuals (HR, 1.24; 95% CI, 1.03-1.44; P = .04), East Asian individuals (HR, 1.76; 95% CI, 1.27-2.25; P = .02), and mixed individuals (HR, 1.39; 95% CI, 1.06-1.71; P = .05), but not Black/African individuals (HR, 1.06; 95% CI, 0.84-1.30; P = .58) or individuals of unknown ethnicity (HR, 1.11; 95% CI, 0.841.40 P = .44; eFigure 3 in the Supplement)
Association of Measured Lipoprotein(a) and LPA GRS With Atherosclerotic Cardiovascular Diseases For individuals of White/European ethnicity without prevalent ASCVD and not using cholesterol-lowering medication (n = 283 540), a 120-nmol/L increase in either measured lipoprotein (a) or LPA GRS was associated with increased risk of incident peripheral arterial disease (HR, 1.25; 95% CI, 1.19-1.31 and 1.34; 95% CI, 1.26-1.42), coronary artery disease (HR, 1.40; 95% CI, 1.371.43 and 1.45; 95% CI, 1.41-1.50), myocardial infarction (HR, 1.32; 95% CI, 1.28-1.36 vs 1.38, 95% CI, 1.33-1.43), ischemic stroke (HR, 1.11; 95% CI, 1.05-1.16 and 1.12, 95% CI, 1.04-1.19), and cardiovascular mortality (HR, 1.09; 95% CI, 1.04-1.16 and 1.09, 95% CI, 1.02-1.16; Figure 2)
Summary
UK Biobank Cohort The UK Biobank is a prospective observational study of approximately 500 000 volunteer adults aged 40 to 69 years recruited from 22 sites across the United Kingdom between 2006 and 2010, with follow-up ongoing. This study included individuals of third-degree relatedness or less (Figure 1).[20] Biochemical measurements, physical examination measurements, and medical histories were assessed at the time of study enrollment. Self-reported ethnicities were categorized as mixed, African/Black, European/White, East Asian, South Asian, and unknown. Main analyses Test the association of the LPA GRS with measured Lp(a) for different ethnic groups. Test the association of the LPA GRS and Lp(a) with incident atherosclerotic cardiovascular disease. Assess whether the addition of continuous levels of measured or Lp(a) or LPA GRS improves risk prediction. 16574 Excluded due to genotyping quality control or missing genotyping data. 73260 Excluded due to prevalent ASCVD and/or use of cholesterol-lowering medication. 17299 Excluded due to non-white/ European ethnicity.
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