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. 2025 Jan 27;32(2):116-127.
doi: 10.1093/eurjpc/zwae271.

Genetically predicted lipoprotein(a) associates with coronary artery plaque severity independent of low-density lipoprotein cholesterol

Shoa L Clarke  1   2   3 , Rose D L Huang  1   4 , Austin T Hilliard  1 , Michael G Levin  5   6 , Disha Sharma  3 , Blake Thomson  7 , Julie Lynch  8 , Philip S Tsao  1 , J Michael Gaziano  4 , Themistocles L Assimes  1   3 ; VA Million Veteran Program
Collaborators, Affiliations

Genetically predicted lipoprotein(a) associates with coronary artery plaque severity independent of low-density lipoprotein cholesterol

Shoa L Clarke et al. Eur J Prev Cardiol. .

Abstract

Aims: Elevated lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease, but the mechanisms of risk are debated. Studies have found inconsistent associations between Lp(a) and measurements of atherosclerosis. We aimed to assess the relationship between Lp(a), low-density lipoprotein cholesterol (LDL-C), and coronary artery plaque severity.

Methods and results: The study population consisted of participants of the Million Veteran Program who have undergone an invasive angiogram. The primary exposure was genetically predicted Lp(a) estimated by a polygenic score. Genetically predicted LDL-C was also assessed for comparison. The primary outcome was coronary artery plaque severity categorized as normal, non-obstructive disease, one-vessel disease, two-vessel disease, and three-vessel or left main disease. Among 18 927 adults of genetically inferred European ancestry and 4039 adults of genetically inferred African ancestry, we observed consistent associations between genetically predicted Lp(a) and obstructive coronary plaque, with effect sizes trending upward for increasingly severe categories of disease. Associations were independent of risk factors, clinically measured LDL-C and genetically predicted LDL-C. However, we did not find strong or consistent evidence for an association between genetically predicted Lp(a) and risk for non-obstructive plaque.

Conclusion: Genetically predicted Lp(a) is positively associated with coronary plaque severity independent of LDL-C, consistent with Lp(a) promoting atherogenesis. However, the effects of Lp(a) may be greater for progression of plaque to obstructive disease than for the initial development of non-obstructive plaque. A limitation of this study is that Lp(a) was estimated using genetic markers and could not be directly assayed nor could apo(a) isoform size.

Keywords: Atherosclerosis; Coronary artery disease; LDL-C; Lipoprotein(a); Polygenic score.

Plain language summary

This study assessed the association between genetic propensity towards higher lipoprotein(a) [Lp(a)] in the blood and the severity of coronary artery plaque seen on clinical angiograms, independent of other factors, including low-density lipoprotein cholesterol (LDL-C). The study was conducted in a large US population using data from the Million Veteran Program.Genetically predicted high Lp(a) was associated with obstructive coronary plaque, but it was not associated with non-obstructive coronary plaque. This association was independent of LDL-C, and the association was greater for more severe forms of disease.The mechanisms of association between Lp(a) and cardiovascular events are debated. Prior studies have shown that Lp(a) does not associate with early markers of atherosclerosis. Our analyses support the idea that Lp(a) plays less of a role in early plaque initiation, but plays a significant role in the progression of plaque towards more severe disease, independent of LDL-C.

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Conflict of interest statement

Conflict of interest: J.A. Lynch reports research grants from the following for-profit organizations outside this submitted work: Alnylam Pharmaceuticals Inc., Astellas Pharma Inc., AstraZeneca Pharmaceuticals LP, Biodesix Inc., Celgene Corporation, Cerner Enviza, GSK PLC, IQVIA Inc., Janssen Pharmaceuticals Inc., Kantar Health, Myriad Genetic Laboratories Inc., Novartis International AG, and Parexel International Corporation through the University of Utah or Western Institute for Veteran Research.

Figures

Figure 1.
Figure 1.. Consort diagram outlining the derivation of the study cohort.
The largest exclusion (n = 25,261) consists of MVP participants that contributed to the GWAS that was used to derive weights for the LDL-C PGS (ref. 41). This exclusion assures no overlap between our study sample and GWAS discovery samples used to generate the PGS. GWAS = genome-wide association study, LDL-C = low-density lipoprotein cholesterol, PGS = polygenic score.
Figure 2.
Figure 2.. Distribution of angiographically observed coronary plaque severity by polygenic score quintile.
A European-ancestry-derived polygenic score for lipoprotein(a) [PGSLp(a)] and a multi-ancestry-derived polygenic score for low-density lipoprotein cholesterol (PGSLDL) were each used to assess the proportion of subjects with each category of coronary plaque within a given PGS quintile. EUR = European ancestry, AFR = African ancestry, PGS = polygenic score.
Figure 3.
Figure 3.. Adjusted associations between lipid polygenic scores and severity of coronary artery plaque.
A, In the European-ancestry cohort, the European-ancestry-derived polygenic score for Lp(a) [PGSLp(a)] showed increasing associations with increasing coronary artery plaque severity independent of risk factors (RFs), clinically observed low-density lipoprotein cholesterol (LDL-C), and genetically predicted LDL-C (PGSLDL). B, In the African-ancestry cohort, the European-ancestry-derived PGSLp(a) showed weaker associations, illustrating that this score lacks predictive value in African-ancestry populations. C-D, A multi-ancestry-derived polygenic score for LDL cholesterol (PGSLDL) showed increasing associations with increasing coronary artery plaque severity independent of RFs and with similar effect sizes in both ancestry groups. The effect sizes attenuated after adjusting for clinically observed LDL-C, but the effects did not meaningfully attenuate with adjustment for genetically predicted Lp(a) [PGSLp(a)]. Odds ratios (OR) and 95% confidence intervals were estimated by multinomial regression and reflect 1 standard deviation (SD) increase in PGS. All models included adjustment for age, sex, and the first 10 ancestry-specific genetic principal components. RFs included hypertension, diabetes, tobacco use, and use of lipid-lowering therapy. EUR = European ancestry, AFR = African ancestry, PGS = polygenic score.
Figure 4.
Figure 4.. Risk of coronary artery plaque associated with genetically predicted high lipoprotein(a) stratified by low-density lipoprotein cholesterol.
The European-ancestry cohort was stratified by highest measured low-density lipoprotein cholesterol (LDL-C). Genetically predicted high lipoprotein(a) [Lp(a)] was defined as the top quintile of the Lp(a) polygenic score (PGSLp(a)), and low was defied as the bottom 4 quintiles. A shows the risk for any plaque (obstructive or non-obstructive) versus normal. B shows the risk for obstructive plaque only versus normal. All models included adjustment for age, sex, hypertension, diabetes, tobacco use, use of lipid-lowering therapy and the first 10 genetic principal components.
Figure 5.
Figure 5.. Genetically predicted Lp(a) and LDL-C associate with coronary artery plaque severity independent of polygenic risk for coronary artery disease.
A-B, The association between a European-ancestry-derived polygenic score for Lp(a) [PGSLp(a)] and coronary plaque severity was compared in a base model (adjusted for age, sex, and genetic principal components) and a model that additionally adjusted for polygenic risk for coronary artery disease (CAD) using a European-ancestry-derived polygenic score for CAD (PGSCAD). In the European-ancestry cohort, adjusting for PGSCAD led to significant attenuation of the effect sizes, but the Lp(a) PGS remained an independent predictor of obstructive coronary plaque. In the African-ancestry cohort, adjusting for PGSCAD led to minimal attenuation in effect sizes. C-D, The same analyses were performed for the multi-ancestry-derived polygenic score for LDL cholesterol (PGSLDL), and a similar pattern was observed. Odds ratios (OR) and 95% confidence intervals were estimated by multinomial regression and reflect 1 standard deviation (SD) increase in PGS. EUR = European ancestry, AFR = African ancestry, PGS = polygenic score.
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Comment in

References

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