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. Author manuscript; available in PMC: 2022 Jan 1.
Published in final edited form as: Arterioscler Thromb Vasc Biol. 2020 Oct 29;41(1):465–474. doi: 10.1161/ATVBAHA.120.315291

Lipoprotein(a) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank

Aniruddh P Patel 1,2,3,4,5, Minxian Wang 4,5, James P Pirruccello 1,2,3,4,5, Patrick T Ellinor 1,2,3,4,5, Kenney Ng 6, Sekar Kathiresan 2,3,4,7, Amit V Khera 1,2,3,4,5
PMCID: PMC7769893  NIHMSID: NIHMS1637324  PMID: 33115266

Abstract

Objective:

Lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease (ASCVD) and new therapies that enable potent and specific reduction are in development. In the largest study conducted to date, we address three areas of uncertainty: (i) the magnitude and shape of ASCVD risk conferred across the distribution of lipoprotein(a) concentrations; (ii) variation of risk across racial and clinical subgroups; (iii) clinical importance of a high lipoprotein(a) threshold to guide therapy.

Approach and Results:

Relationship of lipoprotein(a) to incident ASCVD studied in 460,506 middle-aged UK Biobank participants. Over a median follow-up of 11.2 years, incident ASCVD occurred in 22,401 (4.9%) participants. Median lipoprotein(a) concentration was 19.6 nmol/L (25th-75th percentile 7.6–74.8). The relationship between lipoprotein(a) and ASCVD appeared linear across the distribution, with a hazard ratio of 1.11 (95%CI 1.10–1.12) per 50 nmol/L increment. Substantial differences in concentrations were noted according to race – median values for white, South Asian, black, and Chinese individuals were 19, 31, 75, and 16 nmol/L, respectively. However, risk per 50 nmol/L appeared similar – hazard ratios of 1.11, 1.10, and 1.07 for white, South Asian, and black individuals, respectively. A high lipoprotein(a) concentration defined as ≥150 nmol/L was present in 12.2% of those without and 20.3% of those with pre-existing ASCVD and associated with hazard ratios of 1.50 (95%CI 1.44–1.56) and 1.16 (95%CI 1.05–1.27), respectively.

Conclusions:

Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within primary and secondary prevention contexts, with a linear risk gradient across the distribution. Concentrations are variable across racial subgroups, but the associated risk appears similar.

Keywords: Lipoprotein(a), myocardial infarction, ischemic stroke, Lipids and Cholesterol, Ischemia

Graphical Abstract

graphic file with name nihms-1637324-f0007.jpg

INTRODUCTION:

Lipoprotein(a) [Lp(a)] is comprised of a low-density lipoprotein particle with apolipoprotein B covalently bound to apolipoprotein(a). Circulating concentrations associate with increased risk of atherosclerotic cardiovascular disease (ASCVD).1–4 Early functional work and more recent genetic studies suggest this association is causal, indicating that therapeutic lowering of lipoprotein(a) may reduce ASCVD risk.5–11 Interest in lipoprotein(a) has been intensified by development of an antisense oligonucleotide that potently and specifically reduces lipoprotein(a) concentrations by up to 90%.12–14 The ongoing Lp(a)HORIZON secondary prevention trial (NCT04023552) will test the hypothesis that this therapeutic will decrease ASCVD events among individuals with high lipoprotein(a).15–18 In light of this development, three key areas of uncertainty remain.

First, the magnitude of risk conferred by lipoprotein(a) and whether this risk is linear across the distribution or limited to those with very high concentrations is uncertain. Based on initial observations and a meta-analysis, clinicians often assume a curvilinear shape – where the increased risk is largely restricted to those with very high concentrations – whereas a recent clinical-trial based analysis and genetic studies have suggested a linear relationship.2,19–21

Second, the prognostic importance of increased lipoprotein(a) across racial and clinical subgroups remains uncertain.22 Lipoprotein(a) concentrations are known to vary according to race – more so than any other cardiovascular biomarker.23–26 Beyond the well-described differences in concentration, previous studies suggested the risk conferred by any given increment in lipoprotein(a) may also vary across race.20,21,27–31 With respect to clinical subgroups, some prior studies have suggested the risk associated with lipoprotein(a) is most pronounced in those who also have an increased low-density lipoprotein (LDL) cholesterol concentration and have shown mixed results with respect to degree of risk among individuals with existing ASCVD.25,32

Third, the prevalence and clinical importance of a high lipoprotein(a) concentration (≥150 nmol/L, ~70mg/dL) remains uncertain.20,33–36

A key driver of heterogeneity in the results of prior studies likely relates to the challenges of measuring lipoprotein(a) concentrations.32,33 Because the molecular weight is highly variable across individuals – owing to variable numbers of ‘Kringle IV repeats’ encoded in the LPA gene – mass-based assays are often not reflective of circulating particle number. For this reason, use of well-calibrated assays and reporting in molar units (e.g. nmol/L) is recommended.37

Here, we set out to study these issues in the largest single study to date, examining a multiethnic population of 460,506 participants of the UK Biobank with lipoprotein(a) concentrations measured using a uniform, calibrated assay with excellent concordance with World Health Organization/International Federation of Clinical Chemistry reference material.38 We characterize the shape of the relationship of lipoprotein(a) with incident ASCVD in the context of contemporary clinical practice, assess heterogeneity in risk conferred in racial and clinical subgroups, and determine the prevalence and clinical importance of a high lipoprotein(a) concentration in individuals with or without established ASCVD at time of enrollment.

MATERIAL AND METHODS:

The data that support the findings of this study are available from the UK Biobank upon reasonable request.39

Study population

The UK Biobank is an observational study that enrolled over 500,000 individuals between the ages of 40 and 69 years between 2006 and 2010.40 Here, we studied the subset of 460,506 participants in whom lipoprotein(a) concentrations were measured as part of the study protocol. Data analysis was performed under UK Biobank application #7089 and approved by the Mass General Brigham institutional review board.

Serum lipoprotein(a) concentrations were measured using an immunoturbidimetric assay (Randox Laboratories; Crumlin, County Antrim, United Kingdom using a Beckman Coulter AU5800 Platform.41,42 This assay, although not perfectly isoform insensitive, employs the Denka Seiken method, which has been shown to have excellent concordance with reference material from the World Health Organization/International Federation of Clinical Chemistry (WHO/IFCC), with acceptable levels of bias amongst individuals with very large Lp(a) particles.32,38,43 In order to facilitate comparison with prior studies, conversion from nmol/L to mg/dL was performed by dividing by 2.15, as previously described.44 Briefly, an assessment of 5 standard samples using the Randox assay across a broad range of Lp(a) concentrations indicated a conversion that conversion to milligrams per deciliter can be approximated by dividing values in nanomoles per liter by 2.15 (r2=0.998 for linearity). 79,789 (17.3%) of these individuals had concentration values outside of the assay’s clinically reportable range (3.8 to 189 nmol/L). 46,836 (58.7%) had values below 3.8 nmol/L and 32953 (41.3%) had values above 189 nmol/L. Among individuals in whom lipoprotein(a) was detected above the analytical range, serial dilutions of the sample were carried out, and the sample was reanalyzed.41 A sensitivity analysis that set values below this range to 3.8 nmol/L and above this range to 189.0 nmol/L yielded similar association results. A high lipoprotein(a) concentration was defined as ≥150 nmol/L (70 mg/dL), consistent with the inclusion criteria of the ongoing Lp(a)HORIZON clinical trial.18

To estimate untreated values for LDL and high-density lipoprotein (HDL) cholesterol, measured values for participants reporting use of lipid-lowering medications were adjusted in accordance with average impact on cholesterol concentrations, as we and others have performed previously (Supplemental Table I).45 Although niacin use is known to decrease lipoprotein(a) concentrations, only 77 participants (0.02%) reported use – results of analyses were nearly identical in a sensitivity analysis that excluded these individuals.

Clinical endpoints

ASCVD was defined as a composite of coronary artery disease (myocardial infarction and its acute complications, coronary artery bypass graft surgery or percutaneous angioplasty/stent placement) and ischemic stroke (cerebral infarction due to thrombosis or cerebral atherosclerosis or cerebrovascular syndromes). Affected individuals were identified using a combination of self-reported data confirmed by a trained healthcare professional, hospitalization records, and national procedural and death registries, as previously described.46 The earliest date at which the diagnosis was ascertained was considered as the diagnosis date. Participants were divided into two cohorts, based on the presence or absence of prior ASCVD at time of study enrollment. In individuals without disease at baseline, incident ASCVD events were determined based on first diagnosis of coronary artery disease or ischemic stroke. For individuals with ASCVD at baseline, recurrence of ASCVD was determined based on diagnosis of a second myocardial infarction or revascularization event, first coronary artery disease event in individuals with prior ischemic stroke, or first ischemic stroke event in individuals with prior coronary artery disease.

Statistical analysis

Lipoprotein(a) concentrations were compared across demographic, racial, and clinical subgroups using Kruskal-Wallis and Mann-Whitney U tests. Individuals were binned into percentiles according to lipoprotein(a) concentration, and unadjusted incidence rates of ASCVD were determined within each percentile bin. Subsequent analyses used Cox proportional hazards regression models, including covariates of enrollment age, sex, and self-reported race. In order to display the shape of the relationship between lipoprotein(a) and clinical events, lipoprotein(a) concentrations were modeled using natural cubic splines with median concentration serving as the reference and enrollment age, sex, and self-reported race as covariates; the degrees of freedom for the natural cubic splines of the best fitting model were estimated by the Akaike’s Information Criterion score.47 Additional analyses included assessment of effect estimates in participants according to racial and clinical subgroups and after additional adjustment for the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohorts Equation (PCE) 10-year risk estimate.48

Individuals were stratified according to the presence of ASCVD at time of enrollment and categorized as having high lipoprotein(a) if measured value was above 150 nmol/L or above the racial subgroup-specific 90th percentile. The prognostic importance of lipoprotein(a) concentrations above these thresholds was determined using a Cox proportional hazards regression model, adjusted for enrollment age and sex. The cumulative predicted risk of incident ASCVD at ten years of follow up was quantified using a Cox proportional hazards regression model adjusted for sex and self-reported race, with model standardized to the average of each of the covariates.

Statistical analyses were performed with the use of R software, version 3.5 (R Project for Statistical Computing).

RESULTS:

To understand the relationship between lipoprotein(a) concentrations and risk of ASCVD, we studied 460,506 participants of the UK Biobank with median follow-up of 11.2 years (IQR 10.5 to 11.9). Mean age at enrollment was 57 years, 211,064 (45.8%) were male, and 17,326 (3.8%) had an atherosclerotic cardiovascular disease event prior to enrollment (TABLE 1). 94.3% of participants self-reported as white, but an additional 8,940 (1.9%) participants were South Asian, 7,144 (1.6%) were black, and 1,435 were Chinese (0.3%). For both South Asian and black individuals, this study represents the largest prospective cohort study of lipoprotein(a) to date. Significant differences in lipoprotein(a) concentrations were noted across racial subgroups, with median lipoprotein(a) concentrations of 19, 31, 75, and 16 nmol/L in white, South Asian, black, and Chinese individuals, respectively. Concentrations were also somewhat higher in women than in men, and in individuals who had established ASCVD at the time of enrollment as compared to those who did not (FIGURE 1).

TABLE 1:

Baseline Characteristics

N 460,506
Enrollment Age, years (mean (SD)) 57.0 (8.1)
Male Sex (%) 211,064 (45.8%)
Race (%)
 White 434,058 (94.3%)
 South Asian 8,940 (1.9%)
 Black 7,144 (1.6%)
 Chinese 1,435 (0.3%)
ASCVD before Enrollment (%) 17,326 (3.8%)
Diabetes (%) 25,293 (5.5%)
Hypertension (%) 130,673 (29.6%)
Active Smoker (%) 48,279 (10.5%)
Obesity (%) 111,718 (24.4%)
Family History Heart Disease (%) 201,833 (43.8%)
Family History Stroke (%) 124,222 (27.0%)
LDL-C, mg/dL (mean (SD)) 137.5 (33.6)
Estimated Untreated LDL-C, mg/dL (mean (SD)) 145.6 (33.3)
On Statin at Enrollment (%) 75,114 (16.3%)
Lipoprotein(a), nmol/L (median [IQR]) 19.6 [7.6, 74.8]
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Summary of baseline characteristics of individuals studied in the UK Biobank. SD: standard deviation. IQR: interquartile range.

FIGURE 1:

FIGURE 1:

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Lipoprotein(a) concentrations according to race, sex, and atherosclerotic cardiovascular disease at time of enrollment

Boxplots showing log-transformed lipoprotein(a) distribution by (A) race (Kruskal-Wallis test p<2.2 × 10−16), (B) sex (Mann-Whitney U-test p<2.2 × 10−16), and (C) presence or absence of atherosclerotic cardiovascular disease (ASCVD) at time of enrollment (Mann-Whitney U-test p<2.2 × 10−16). Dimensions of the box capture the 25th to 75th percentiles, and whiskers capture an additional one interquartile range.

We next quantified the risk of incident ASCVD across the spectrum of observed lipoprotein(a) concentrations, binning individuals into percentiles of the lipoprotein(a) distribution. With over 5.1 million person-years (PY) of follow-up time, we noted 22,401 incident ASCVD events – 16,853 coronary artery disease events and 6,325 ischemic stroke events. The gradient in risk according to lipoprotein(a) across percentile bins was largely linear, with no evidence of a threshold effect leading to a sharp uptick in risk for those with very high concentrations. Incidence rates were 4.4 per 1000 PY for those in the lowest percentile (95% confidence interval (CI) 3.8–5.0) versus 7.3 per 1000PY for those in the highest percentile (95%CI 6.6–8.1) (FIGURE 2A). The adjusted hazard ratio for those in the top percentile – with median lipoprotein(a) concentration of 394 nmol/L – versus those in the middle quintile was 1.87 (95%CI 1.68–2.08). To put the risk gradient observed across percentiles of the lipoprotein(a) distribution into context, we conducted similar analyses for estimated untreated LDL and HDL cholesterol concentrations noting similar magnitudes of effect. For LDL cholesterol, as compared to those in the middle quintile, those in the top percentile had an adjusted hazard ratio of 2.20 (95%CI 2.00–2.41) (Supplemental Figure I). Similarly, for HDL cholesterol, we observed adjusted hazard ratios comparing bottom percentile to middle quintile of 3.06 (95%CI 2.59–3.60) for women and 1.56 (95%CI 1.36–2.80) for men (Supplemental Figure I)

FIGURE 2:

FIGURE 2:

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Incidence and risk of atherosclerotic cardiovascular disease according to lipoprotein(a) concentration

A: Incidence rates per 1000 person-years with corresponding 95% confidence intervals of atherosclerotic cardiovascular disease events grouped by percentile of the lipoprotein(a) distribution. B: Smoothed adjusted hazard ratio and 95% confidence intervals of individuals with a given lipoprotein(a) concentration with respect to the risk in an individual with the median lipoprotein(a) concentration in the population (19.6 nmol/L), estimated using a Cox proportional hazards regression model with covariates of enrollment age, sex, self-reported race, and lipoprotein(a) concentration modeled using cubic natural splines.

For lipoprotein(a), we next used cubic natural splines to model the relationship of lipoprotein(a) concentrations with incident ASCVD, again noting a largely linear gradient in risk (FIGURE 2B). As expected, given minimal correlation of lipoprotein(a) concentrations with the Pooled Cohorts Equation risk estimate (Pearson correlation 0.024), these estimates were minimally affected by additional inclusion of the Pooled Cohorts Equation risk estimate as a covariate (Supplemental Figure II). Similarly, we noted minimal attenuation of risk when additionally adjusting for hypertension, diabetes, smoking, total cholesterol and history of prior cardiovascular disease (Supplemental Figure II).

We observed a hazard ratio of 1.11 (95%CI 1.10–1.12) per 50 nmol/L increment in lipoprotein(a) concentration in the overall study population and next set out to assess the consistency of this effect estimate across important clinical subgroups. There was a modest but statistically significant difference in risk estimates observed for individuals without ASCVD at baseline (HR 1.10, 95%CI 1.09–1.11) compared to individuals with ASCVD at baseline (HR 1.04 95%CI 1.02–1.06). Adjusting for statin use at enrollment attenuated this difference in risk between individuals without (HR 1.10, 95%CI 1.09–1.11) and with (HR 1.05, 95%CI 1.03–1.08) ASCVD at baseline. Among individuals without ASCVD, those taking statins at enrollment experienced a less pronounced lipoprotein(a)-associated risk of ASCVD (HR 1.07, 95%CI 1.05–1.08) relative to those who were not taking a statin (HR 1.11, 95%CI 1.10–1.13). ASCVD risk estimates appeared to be similar across sexes and in other clinical subgroups (FIGURE 3).

FIGURE 3:

FIGURE 3:

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Risk associated with increased lipoprotein(a) according to racial and clinical subgroups

Hazard ratios with corresponding 95% confidence intervals and p values for risk of atherosclerotic cardiovascular disease (ASCVD) events per 50 nmol/L increase in lipoprotein(a) are reported based on a Cox proportional hazards regression models with covariates of enrollment age, sex, and self-reported race. Subgroup analyses were performed with cohorts splitting based on presence or absence of variable of interest. Additionally, an interaction p value was computed to examine the significance of interaction between variable of interest and lipoprotein(a) concentration in influencing ASCVD risk. Median estimated unadjusted low-density lipoprotein (LDL) cholesterol concentration: 143.2 mg/dL.

We next studied the prevalence and clinical importance of high lipoprotein(a) concentrations, defined as ≥ 150 nmol/L (~70mg/dL) (Supplemental Table II). Among individuals without baseline ASCVD, a high lipoprotein(a) concentration was identified in 53,905 of 443,180 individuals (12.2%) (FIGURE 4). An incident ASCVD event occurred in 3,290 (6.1%) of these individuals versus 16,643 (4.3%) in the remainder of the population, corresponding to an adjusted hazard ratio of 1.50 (95%CI 1.44–1.56). This increased risk was noted for both incident coronary artery disease (HR 1.63, 95%CI 1.56–1.70) and ischemic stroke (HR 1.16, 95%CI 1.07–1.25) (FIGURES 4 & 5). Among individuals with ASCVD at the time of enrollment, a high lipoprotein(a) concentration was identified in 3,510 of 17,326 (20.3%) individuals and was associated with an adjusted hazard ratio of 1.16 (95% CI 1.05 to 1.27) for a second ASCVD event. Within this secondary prevention population, a statistically significant increase in risk was noted for coronary artery disease (HR 1.23, 95%CI 1.10–1.37, but not for ischemic stroke (HR 0.93, 95%CI 0.77–1.12) (FIGURES 4 & 5). Sensitivity analyses using a cutoff of 175 nmol/L yielded similar results (Supplemental Figure III). Graded increases in cumulative incidence of ASCVD were seen across subgroups of individuals with lipoprotein(a) concentrations greater than 150 nmol/L (Supplemental Figure IV).

FIGURE 4:

FIGURE 4:

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Prevalence and clinical importance of high lipoprotein(a) concentrations

Histogram of counts of individuals per given lipoprotein(a) [Lp(a)] concentration bin, with red shaded region designating above cutoff of 150 nmol/L (~70 mg/dL) in individuals without (A) and with (C) prior atherosclerotic cardiovascular disease (ASCVD) at enrollment (distribution truncated at 400 nmol/L). Cumulative incidence of initial (B) or subsequent (D) ASCVD events over length of follow-up stratified by lipoprotein(a) cutoff of 150 nmol/L, estimated using Cox proportional hazards regression model standardized to the average of the enrollment age and sex, for individuals without (B) and with (D) prior ASCVD at enrollment, respectively.

FIGURE 5:

FIGURE 5:

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Lipoprotein(a) association analysis by concentration, composite and individual component endpoints

Hazard ratios with corresponding 95% confidence intervals and p values for composite atherosclerotic cardiovascular disease (ASCVD) and component endpoints, comparing individuals with lipoprotein(a) concentrations above and below cutoff of 150 nmol/L (~70 mg/dL), calculated using Cox proportional hazards regression models with covariates of enrollment age, sex, and self-reported race. MI: Myocardial infarction.

An analysis that predicted risk of ASCVD at ten years of follow-up noted similar conclusions. Among those without ASCVD at the time of enrollment, the cumulative ten-year risk of an ASCVD event was 4.2% in those with a high lipoprotein(a) concentration versus 2.8% in those in the remainder of the distribution. Similarly, among those with ASCVD at time of enrollment, the ten-year risk for incidence of a second event was 14.7% in those with a high lipoprotein(a) concentration versus 12.9% for those in the remainder of the distribution. Importantly, these risk estimates reflect disease rates in the context of contemporary clinical practice, which includes recommended screening and therapies for prevention of cardiovascular disease.

Finally, we examined the associations of lipoprotein(a) and ASCVD in different racial subgroups. Despite striking differences in distributions of lipoprotein(a) concentrations, the estimated hazard ratio per 50 nmol/L increase for white (HR 1.11, 95%CI 1.10–1.12), South Asian (HR 1.10, 95%CI 1.04–1.16), and black (HR 1.07, 95%CI 1.00–1.15) individuals were similar (P-heterogeneity = 0.60). Although the absolute incident rates of ASCVD varied across racial groups, the relative risk gradient across the lipoprotein(a) concentration distribution appeared similar across white, South Asian, and black individuals (Supplemental Figure V). Within the context of a uniform 150 nmol/L threshold lipoprotein(a) value, we again estimated similar risks for ASCVD among white (HR 1.51, 95%CI 1.45–1.57), South Asian (HR 1.37, 95%CI 1.05–1.81), and black (1.13, 95%CI 0.84–1.50) individuals (P-heterogeneity 0.15). Given the widely varying lipoprotein(a) concentrations in different racial subgroups, an alternate approach is to define race-specific thresholds such as >90th percentile of the distribution, corresponding to thresholds of 168.2 nmol/L, 139.5 nmol/L, and 211.7 nmol/L for white, South Asian, and black individuals, respectively. Even in this context, white (HR 1.52, 95%CI 1.46–1.59), South Asian (HR 1.35, 95%CI 1.03–1.78), and black (HR 1.51, 95%CI 1.05–2.18) individuals with lipoprotein(a) concentrations above the 90th percentile experienced similar magnitudes of increased risk (P-heterogeneity 0.93) (Figure 6) for ASCVD.

FIGURE 6:

FIGURE 6:

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Lipoprotein(a) association analysis by racial subgroup

Hazard ratios with corresponding 95% confidence intervals and p values for first incidence of composite atherosclerotic cardiovascular disease (ASCVD) end point across different racial subgroups, computing risk of disease for every 50 nmol/L increase in lipoprotein(a) [Lp(a)], comparing individuals with lipoprotein(a) concentrations above and below cutoff of 150 nmol/L and race-specific 90th percentiles (white: ≥168.2 nmol/L, South Asian: ≥139.5 nmol/L, and black ≥211.7 nmol/L), calculated using Cox proportional hazards regression models with covariates of enrollment age, and sex. Owing to incident ASCVD events in only 27 of 1,415 individuals of Chinese ancestry, reliable effect estimation was not possible in this subgroup.

DISCUSSION:

In the largest study to date of lipoprotein(a), we observe that higher concentrations predict risk of incident ASCVD among middle-aged adults. These results build on previous efforts to understand the relationship of lipoprotein(a) with ASCVD risk in several key ways. First, we assess risk conferred by lipoprotein(a) for incident ASCVD events in a large number of individuals from a national biobank with a median follow-up of 11.2 years, enabling analyses of important racial and clinical subgroups. Second, lipoprotein(a) concentrations were uniformly measured using an immunoassay with excellent concordance with World Health Organization/International Federation of Clinical Chemistry reference material. Third, estimates of cardiovascular risk are in the context of contemporary clinical care, including therapy with statins in a significant proportion of participants.

Although clinicians often believe that the risk associated with lipoprotein(a) is primarily restricted to those with very high concentrations, we demonstrate a linear relationship with risk of ASCVD. These results, distinct from early studies,2 are largely in keeping with the conclusions of more recent studies that have similarly used well-calibrated immunoassays and genetic analyses. The gradient of risk conferred across the lipoprotein(a) distribution was similar to that of traditional lipid biomarkers, including HDL or LDL cholesterol concentrations.

With respect to the ongoing Lp(a)HORIZON secondary prevention clinical trial, we note that 20.3% of participants with ASCVD at enrollment have lipoprotein(a) concentrations greater than 150 nmol/L, which approximates the inclusion threshold of 70 mg/dL. These individuals had modestly increased risk of recurrent ASCVD events when compared to those in the remainder of the distribution – adjusted hazard ratio of 1.16. Importantly, this study is not intended to predict results of the trial and the modest hazard ratio observed does not indicate that the trial is likely to fail. For example, cholesterol-lowering medications have been proven to reduce recurrent ASCVD events even in individuals with LDL cholesterol concentrations at or below the population average.49,50 However, taken together with recent genetic modeling studies, a clinically meaningful decrease in risk of ASCVD is likely to require large absolute reductions in lipoprotein(a) concentrations.9,35

Furthermore, the size of this study population without established ASCVD or statin therapy and length of follow up provides insight into the role of lipoprotein(a) in primary prevention. Notably, among the 12.2% of the participants without ASCVD at enrollment who have a lipoprotein(a) concentration ≥150 nmol/L, we observe a more substantial increase in relative risk (HR 1.50, 95%CI 1.44–1.56) compared to individuals with ASCVD at baseline (HR 1.16, HR 1.05–1.27). This validates findings from prior studies and could form the basis of future clinical trials aimed at primary prevention.6,34

The risk conferred by a given increment in lipoprotein(a) concentrations was broadly similar across racial and clinical subgroups. For example, although black participants had a median lipoprotein(a) concentration quadruple that of white participants, the hazard ratios per 50 nmol/liter increment were similar (P-heterogeneity = 0.60). Furthermore, the risks conferred by a threshold of 150 nmol/L or a race-specific 90th percentile were statistically similar across the three racial subgroups. Consistent with prior smaller studies, a uniform high cutoff of lipoprotein(a) led to a marginally lower risk estimate in black individuals relative to other subgroups.19,20 The use of race-specific percentiles in this study led to more similar risk estimates across the three racial subgroups, however the absolute differences in these approaches to thresholds remained small. This suggests that the use of a single threshold would lead to marked enrichment for black and South Asian individuals, all else being equal, but may be clinically sensible given the logistical challenges of using race-specific biomarker cutoffs.

These results should be interpreted within the context of potential limitations. First, we did not consider the relationship of genetic variants with lipoprotein(a) concentrations and risk of ASCVD. However, prior analyses indicate that the risk conferred by lipoprotein(a) is almost completely captured by circulating concentrations, with minimal incremental value of common genetic variants or the number of apo(a) Kringle IV repeats.5,51 Second, lipoprotein(a) was measured using a widely available immunoassay employing the isoform-sensitive Denka Seikan method which is not fully isoform-insensitive. Therefore, it may lead to errors in measurement among individuals with large lipoprotein(a) isoforms, unlike the isoform insensitive gold-standard assay from Northwest Lipid Metabolism Diabetes Research Laboratory. Third, UK Biobank participants were recruited at age 40–69 years and mostly white, raising the possibility of selection bias that limits generalizability to younger patients or to individuals from other racial groups. Fourth, disease endpoints were ascertained through participant self-report, diagnosis codes from inpatient admissions, and national procedure and death registries.

CONCLUSION:

Lipoprotein(a) concentrations predict incident ASCVD among middle-aged adults within both primary and secondary prevention contexts, with a linear gradient in risk across the distribution. Concentrations are highly variable across racial subgroups, but the increased risk associated with any given increment in lipoprotein(a) concentration appears similar.

Supplementary Material

Supplemental Material

HIGHLIGHTS:

  • A linear risk in risk of atherosclerotic cardiovascular disease (ASCVD) with higher lipoprotein(a) concentrations is observed within the context of modern clinical care in a large, prospective cohort study.

  • Relative risk estimates for individuals with lipoprotein(a) concentrations above 150 nmol/L (~70 mg/dL) relative to the rest of the population are more pronounced in individuals without ASCVD at baseline, compared to those with prior history of ASCVD.

  • Different racial subgroups have similar ASCVD risk estimates when using a uniform (≥150 nmol/L) or race-specific percentile threshold for elevated lipoprotein(a) concentration.

ACKNOWLEDGEMENTS:

We are indebted to the UK Biobank and its participants who provided biological samples and data for this analysis. Work was performed under UK Biobank application #7089. Drs. Patel, Wang, and Khera had full access to the study data and take responsibility for its integrity and data analysis.

FUNDING:

Funding support was provided by grant T32HL007208 from the National Heart, Lung, and Blood Institute (A.P.P.), John S. LaDue Memorial Fellowship for Cardiovascular Research (J.P.P.), grant 14CVD01 Fondation Leducq (P.T.E.), grants 1RO1HL092577, R01HL128914, K24HL105780 from the National Heart, Lung, and Blood Institute (P.T.E), grant 18SFRN34110082 from the American Heart Association (P.T.E.), an institutional grant from the Broad Institute of MIT and Harvard (BroadIgnite, to A.V.K.), and grant 1K08HG010155 (to A.V.K.) from the National Human Genome Research Institute, a Hassenfeld Scholar Award from Massachusetts General Hospital (to A.V.K.), and a sponsored research agreement from IBM Research (A.V.K.).

DISCLOSURES:

P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. S.K. is an employee of Verve Therapeutics, and holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics. He is a member of the scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; he has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, and Medscape; he reports patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). K.N. is an employee of IBM Research. A.V.K. has served as a consultant to Sanofi, Medicines Company, Amgen, Maze Pharmaceuticals, Navitor Pharmaceuticals, and Color Genomics; received speaking fees from Illumina, the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research, and reports a patent related to a genetic risk predictor (20190017119).

ABBREVIATIONS:

Lp(a)

Lipoprotein(a)

ASCVD

Atherosclerotic cardiovascular disease

MI

Myocardial infarction

LDL

Low-density lipoprotein

HDL

High-density lipoprotein

PCE

Pooled cohorts equations

Footnotes

The remaining authors have no disclosures.

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