Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study

Verbeek, Rutger; Boekholdt, S. Matthijs; Stoekenbroek, Robert M.; Hovingh, G. Kees; Witztum, Joseph L.; Wareham, Nicholas J.; Sandhu, Manjinder S.; Khaw, Kay‐Tee; Tsimikas, Sotirios

doi:10.1194/jlr.p066258

Cited by 24 publications

(23 citation statements)

References 39 publications

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“…9 In fact, in the several Copenhagen studies published to date in general populations, from which the EAS recommendations were actually derived, the data most strongly support a risk starting at >≈20 mg/dL or the 67th percentile. 2,19,20 Consistent with these data, in the Emerging Risk Factor Collaboration, Lp(a) levels displayed a curvilinear relationship, with the curve rising very slowly until ≈24 mg/dL, then rising almost linearly with increasing levels.…”

Section: Discussionmentioning

confidence: 96%

“…11 Finally, in a nested case-control study from EPIC-Norfolk, using a unique methodology of 2 different assays in the same population, the 80% thresholds were at 36 and 24 mg/dL for the Randox and an in-house research Lp(a) ELISA developed at University of California San Diego (UCSD; 21 this is not the assay the UCSD Medical Center uses), respectively, a level at which the highest risk of coronary artery disease was also noted. 9 This suggests that the >30 mg/dL cutoff used in most laboratories is a more accurate reflector of risk in primary prevention populations, a number that was first suggested over 35 years ago. 22 Regarding appropriate units, some European laboratories report data as mg/L, so that this lower level cutoff would be >300 mg/L.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, setting thresholds and levels at which one might assign risk has to take into account the prevalence of the extent of CVD and that thresholds may need to be different for the general community versus actual patients. 9 Another layer of complexity in establishing Lp(a) cutoffs that has not been fully understood is that significant racial and ethnic differences exist in Lp(a) levels, with the highest levels generally in descending order being present in Blacks, Asian Indians, Caucasians, Hispanics, and East Asians. [26][27][28] It was previously thought that Blacks do not have the same risk of CAD and stroke from Lp(a) unless they carried small isoforms, but a recent large study from the ARIC study (Atherosclerosis Risk in Communities) 29 with 20-year follow-up suggests similar risk between Whites and Blacks.…”

Section: Downloaded Frommentioning

confidence: 99%

“…However, in epidemiological and Mendelian randomization studies performed in primary care populations with no prior CVD, including from Copenhagen, increased CVD risk actually starts as low as 25 to 30 mg/dL. [1][2][3]9 In secondary prevention populations consisting of patients with prior CVD that are optimally treated with statins and antiplatelet agents, recurrent events seem to begin at values >50 mg/dL. [10][11][12] Lp(a) is composed of apolipoprotein(a) [apo(a)] covalently bound to apolipoprotein B (apoB)-100 of a low-density lipoprotein (LDL)-like particle.…”

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confidence: 99%

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Prevalence of Elevated Lp(a) Mass Levels and Patient Thresholds in 532 359 Patients in the United States

Varvel

McConnell

Tsimikas

2016

ATVB

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133

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Objective-Elevated lipoprotein(a) [Lp(a)] is a causal, independent risk factor for cardiovascular disease and aortic stenosis.We aimed to define the prevalence and patient thresholds of elevated Lp(a) levels in the United States. Approach and Results-We analyzed Lp(a) levels in 532 359 subjects from 2 data sets: (1) in 531 144 subjects from a referral laboratory and (2) in 915 patients from a tertiary referral center. Lp(a) mass levels were measured by immunoturbidometric assays in both centers and expressed as mg/dL. At the referral laboratory, the median age (interquartile range) of the subjects was 57.0 (46-67) years, and 51.9% were female. Lp(a) levels were skewed rightward as expected. The mean±SD levels were 34.0±40.0 mg/dL, and median (interquartile range) levels were 17 (7-47) mg/dL, with range 0 to 907 mg/dL. Lp(a) levels at 75%, 80%, 90%, 95%, 99%, and 99.9% percentiles were >47, >60, >90, >116, >180, and >245 mg/dL, respectively. At the referral laboratory, Lp(a) levels >30 and >50 mg/dL were present in 35.0% and 24.0% of subjects, respectively, and at the tertiary referral center, 39.5% and 29.2%, respectively. Females had higher mean (SD) (37. Results Data From the Referral LaboratoryRelationship of Lp(a) to Lipid, Lipoprotein, and High Sensitivity C-Reactive Protein Levels Over the 5-year period, a total of 531 144 Lp(a) measurements, with accompanying information on lipid parameters and high sensitivity C-reactive protein (hsCRP), from individual patients in the referral laboratory were available. The median age of all the subjects was 57.0 (46-67), 51.9% were female, and the mean body mass index was 29.7±6.7. Tables 1 and 2 display the relationship of Lp(a) mass, in quintiles and as Lp(a) <30 mg/dL versus >30 mg/dL and <50 mg/dL versus >50 mg/dL, to mean levels of LDL cholesterol (LDL-C), estimated LDL-C corrected for Lp(a) cholesterol, total cholesterol, high-density lipoprotein cholesterol, triglycerides, apoB-100, and non-high-density lipoprotein cholesterol. The mean±SD Lp(a) levels were 34.0±40.0 mg/dL and median (interquartile range) levels were 17 (7-47) mg/dL, with range 0 to 907 mg/ dL. Lp(a) levels at 75%, 80%, 90%, 95%, 99%, and 99.9% percentiles were >47, >60, >90, >116, >180, and >245 mg/dL, respectively. Females had higher mean (SD) (37. Lp(a) levels >30 and >50 mg/dL were present in 35.0% and 24.0% of subjects, respectively. Evaluating Lp(a) in quintiles, LDL-C linearly increased from 99.1 to 108.6 mg/dL. In contrast, removing the Lp(a) cholesterol component of Lp(a) showed that the corrected LDL-C was actually decreasing from 98.1 to 78.5 mg/dL with increasing Lp(a) mass. Total cholesterol, high-density lipoprotein cholesterol, apoAI, and non-high-density lipoprotein cholesterol were all increasing with increasing Lp(a), but triglycerides decreased across quintiles. hsCRP was also increasing linearly with Lp(a) quintiles or Lp(a) cutoffs of >30 and >50 mg/dL (Tables 1 and 2). Frequency Distribution of Lp(a), LDL-C, and ApoBAs expected, Lp(a) mass levels were skewed rightward (...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Prevalence of Elevated Lp(a) Mass Levels and Patient Thresholds in 532 359 Patients in the United States

Varvel

McConnell

Tsimikas

2016

ATVB

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133

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“…It is estimated that 20% of the population has Lp(a) levels above 50 mg/dL and that the risk for CVD is increased by 2‐ to 2.5‐fold in individuals with levels above the 90th percentile . However, the cut‐off is assay‐dependant and some studies suggested a cut‐off of 24 mg/dL or 36 mg/dL in populational studies …”

Section: Introductionmentioning

confidence: 99%

Prognostic value of elevated lipoprotein(a) in patients with acute coronary syndromes

Gencer

Rigamonti

Nanchen

et al. 2019

Eur J Clin Investigation

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Background Minimal lipoprotein(a) [Lp(a)] target values are advocated for high‐risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS). Materials and methods Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicentre Swiss prospective cohort. Associations between elevated Lp(a) ≥30 mg/dL (cut‐off corresponding to the 75th percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1 year, defined as a composite of cardiac death, myocardial infarction or stroke, were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low‐density lipoprotein cholesterol [LDL‐C], high‐density lipoprotein cholesterol [HDL‐C] and triglycerides. Results Lp(a) levels range between 2.5 and 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥30 mg/dL. Patients with elevated Lp(a) were more likely to be of female gender and to have higher levels of total cholesterol, LDL‐C, HDL‐C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL‐C target <1.8 mmol/L at 1 year (HR 1.71, 95% CI 1.13‐2.58, P = 0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64‐1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52‐1.28, P > 0.20) or standardized continuous variables (0.98, 95% CI 0.82‐1.19 for each increase of standard deviation). Conclusions Our real‐world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL‐C targets 1 year after ACS.

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

et al. 2021

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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.

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Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study

Cited by 24 publications

References 39 publications

Prevalence of Elevated Lp(a) Mass Levels and Patient Thresholds in 532 359 Patients in the United States

Prevalence of Elevated Lp(a) Mass Levels and Patient Thresholds in 532 359 Patients in the United States

Prognostic value of elevated lipoprotein(a) in patients with acute coronary syndromes

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

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