Abstract
Background:
Coronary atherosclerotic burden and adverse coronary heart disease (CHD) events are related phenotypes with likely shared genetic etiology.
Methods:
We analyzed 6,021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of PRS for CHD (PRSCHD) with multiple measures of CAD severity. We assessed the interplay between PRSCHD and pathogenic/likely pathogenic (P/LP) variants in three familial hypercholesterolemia (FH) genes. We performed mediation analyses to explore whether CAD severity mediated the association of PRSCHD with prevalent CHD and incident MI.
Results:
A 1-SD increase in PRSCHD was associated with multiple measures of CAD severity, including the log Gensini score (β=0.31; 95% CI, 0.28 to 0.33). Carrying a P/LP FH variant was associated with a higher log Gensini score after adjustment for PRSCHD (β=0.21; 95% CI, 0.03 to 0.38). PRSCHD was associated with incident MI over a mean follow-up of 9.2 years (HR=1.20; 95% CI, 1.13 to 1.27; P=5×10−10), and the Gensini score mediated 90% of this association.
Conclusions:
PRSCHD was associated with multiple measures of CAD severity. The association of PRSCHD with incident MI was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the two phenotypes.
Keywords: Polygenic risk scores, coronary artery disease
Introduction
Genome-wide association studies (GWAS) have identified multiple risk loci for coronary heart disease (CHD)1–5, enabling the development of polygenic risk scores (PRS) for CHD (PRSCHD)6–9. Previous studies have revealed distinct genetic associations with atherosclerotic burden in coronary arteries and adverse CHD events10–12, suggesting that the two phenotypes, whilst related, may have different genetic susceptibility factors. This observation is supported by the concept of plaque “vulnerability” wherein myocardial infarction (MI) can occur in the absence of a significant coronary atherosclerotic burden13.
Early studies on the association of PRSCHD with angiographic severity of coronary artery disease (CAD) focused on multivessel disease or the number of stenotic arteries (≥50%). They were mostly limited to patients with risk factors for atherosclerosis or a history of CAD14–16. A later study showed that this association is driven by an increased overall burden of atherosclerosis in all coronary arteries rather than specific plaque characteristics, although it remains unclear to what extent the association of PRSCHD with adverse CHD events is mediated by CAD severity17.
In this study, we tested a recent multi-ancestry PRSCHD for association with multiple measures of CAD severity and incident MI after first angiography. We investigated the interplay between PRSCHD and pathogenic and likely pathogenic (P/LP) variants in familial hypercholesterolemia (FH) genes. Lastly, we tested whether the association of PRSCHD with CHD events is mediated by CAD severity.
Methods
Detailed methods are available in the Supplemental Material. The Mayo Clinic Institutional Review Board approved the study protocol. All participants provided consent. To apply for access to the Mayo Clinic Biobank, contact biobank@mayo.edu. A Mayo Clinic researcher must be included as a collaborator on all projects, due to the specifics of the informed consent language. Due to institutional review board regulations, individual-level data from the Mayo Vascular Disease Biorepository are unavailable.
Results
We analyzed 6,021 Mayo Clinic patients: 3,586 from MCB and 2,435 from VDB. The mean age was 70.3 years, 33% were female, and 69% had ASCVD at first angiography. Hypertension was the most common ASCVD risk factor (Table 1). Overall, 4,385 patients (73%) had angiographic CAD, and LAD was the most affected coronary artery (58%). 3,815 (63%) had severe stenosis and 1,418 (24%) had 3-vessel disease.
Table 1.
Characteristics of patients at the time of first coronary angiography and summary of coronary angiography variables.
| Characteristic | MCB (n=3,586) | VDB (n=2,435) | Combined (n=6,021) |
|---|---|---|---|
|
| |||
| Demographics | |||
| Age, years | 70.9 ± 10.2 | 69.5 ± 11 | 70.3 ± 10.6 |
| Female | 1,308 (36.5%) | 689 (28.3%) | 1,997 (33.2%) |
|
| |||
| Risk factors | |||
| Type 2 diabetes | 848 (23.6%) | 602 (24.7%) | 1,450 (24.1%) |
| Hypertension | 2,331 (65.0%) | 2,093 (86.0%) | 4,424 (73.5%) |
| Current smoker | 153 (4.3%) | 799 (32.8%) | 952 (15.8%) |
| Past smoker | 1,541 (43.0%) | 678 (27.8%) | 2,219 (36.9%) |
| Family history of CHD | 1,202 (33.5%) | 2,106 (86.5%) | 3,308 (54.9%) |
| Dyslipidemia | 1,656 (46.2%) | 2,125 (87.3%) | 3,781 (62.8%) |
| Statin treatment | 2,827 (78.8%) | 1,792 (73.6%) | 4,619 (76.7%) |
|
| |||
| ASCVD | 1,965 (54.8%) | 2,170 (89.1%) | 4,135 (68.7%) |
| CHD | 1,764 (49.2%) | 1,882 (77.3%) | 3,646 (60.5%) |
| PAD | 31 (0.9%) | 585 (24.0%) | 616 (10.2%) |
| AAA | 51 (1.4%) | 250 (10.3%) | 297 (4.9%) |
| CAS | 231 (6.4%) | 549 (22.5%) | 780 (13.0%) |
| CVD | 259 (7.2%) | 346 (14.2%) | 591 (9.8%) |
|
| |||
| Coronary angiograms per person | 1.6 ± 1.3 | 1.9 ± 1.8 | 1.7 ± 1.6 |
| Coronary arteries with ≥50% stenosis | 2,410 (67.2%) | 1,975 (81.1%) | 4,385 (72.8%) |
| Left main coronary artery | 378 (10.5%) | 488 (20.0%) | 866 (14.4%) |
| LAD | 1,937 (54.0%) | 1,580 (64.9%) | 3,517 (58.4%) |
| Circumflex | 1,081 (30.1%) | 1,065 (43.7%) | 2,146 (35.6%) |
| RCA | 1,479 (41.2%) | 1,516 (62.3%) | 2,995 (49.7%) |
| Coronary arteries with ≥70% stenosis | 2,042 (56.9%) | 1,773 (72.8%) | 3,815 (63.4%) |
| Left main coronary | 209 (5.8%) | 294 (12.1%) | 503 (8.4%) |
| LAD | 1,476 (41.2%) | 1,270 (52.2%) | 2,746 (45.6%) |
| Circumflex | 758 (21.1%) | 794 (32.6%) | 1,552 (25.8%) |
| RCA | 1,173 (32.7%) | 1,266 (52.0%) | 2,439 (40.5%) |
| 3-vessel disease | 639 (17.8%) | 779 (32.0%) | 1,418 (23.6%) |
| Gensini score | 42.5 ± 44.1 | 63.7 ± 59.5 | 51.0 ± 51.9 |
Age, number of angiograms per person, and Gensini score are reported as mean ± SD. Abbreviations: ASCVD: atherosclerotic cardiovascular disease; AAA: abdominal aortic aneurysm; CAS: carotid artery stenosis; CHD: coronary heart disease; CVD: cerebrovascular disease; LAD: left anterior descending; MCB: Mayo Clinic Biobank; PAD: peripheral artery disease; RCA: right coronary artery; VDB: Vascular Disease Biorepository.
Associations of PRSCHD with CAD severity
A 1-SD increase in PRSCHD was associated with angiographic CAD (OR=1.72; 95% CI, 1.62 to 1.84; P=1×10−62), 3-vessel disease (OR=1.58; 95% CI, 1.48 to 1.68; P=5×10−42), and severe stenosis (OR=1.74; 95% CI, 1.64 to 1.84; P=3×10−73) (Table 2). In a subset of 3,646 patients with a clinical CHD diagnosis at first angiography, 1,134 had 3-vessel disease and 2,955 had severe stenosis. In this group, PRSCHD was associated with both 3-vessel disease (OR=1.41; 95% CI, 1.30 to 1.52; P=3×10−18) and severe stenosis (OR=1.59; 95% CI, 1.45 to 1.74; P=2×10−23). We observed similar associations of PRSCHD with 3-vessel disease and severe stenosis in a subgroup of 4,135 patients with clinical ASCVD diagnosis at first angiography (Table 2).
Table 2.
Associations of PRSCHD with CAD, 3-vessel disease, severe stenosis, percent stenosis in coronary arteries, and the Gensini score.
| Variable | OR (95% CI) | P | AUCBasic | AUCBasic + PRS |
|---|---|---|---|---|
|
| ||||
| All patients (n=6,021) | ||||
| CAD | 1.72 (1.62–1.84) | 1×10−62 | 0.66 | 0.71 |
| 3-vessel disease | 1.58 (1.48–1.68) | 5×10−42 | 0.65 | 0.69 |
| Severe stenosis | 1.74 (1.64–1.84) | 3×10−73 | 0.65 | 0.70 |
|
CHD diagnosis at first angiography (n=3,646) | ||||
| 3-vessel disease | 1.41 (1.30–1.52) | 3×10−18 | 0.61 | 0.64 |
| Severe stenosis | 1.59 (1.45–1.74) | 2×10−23 | 0.62 | 0.66 |
|
ASCVD diagnosis at first angiography (n=4,135) | ||||
| 3-vessel disease | 1.43 (1.33–1.54) | 1×10−21 | 0.61 | 0.64 |
| Severe stenosis | 1.62 (1.50–1.76) | 1×10−31 | 0.60 | 0.66 |
|
| ||||
| β (95% CI) | P | R 2 Basic | R 2 Basic + PRS | |
|
Percent stenosis and severity (n=6,021) | ||||
| Left main coronary artery | 4.4 (3.8–5.0) | 4×10−44 | 0.067 | 0.097 |
| LAD | 7.4 (6.7–8.2) | 7×10−79 | 0.061 | 0.114 |
| Circumflex | 6.7 (5.9–7.6) | 2×10−55 | 0.054 | 0.092 |
| RCA | 8.6 (7.7–9.4) | 4×10−81 | 0.086 | 0.140 |
| All coronary arteries (max. stenosis) | 8.0 (7.3–8.8) | 5×10−104 | 0.082 | 0.151 |
| Gensini score (log scale) | 0.31 (0.28–0.33) | 4×10−114 | 0.108 | 0.181 |
OR and β are given for a 1-SD increase in PRSCHD. AUCBasic + PRS and R2Basic + PRS correspond to the full models and AUCBasic and R2Basic to models without PRSCHD.
AUC: Area under the curve; CAD: coronary artery disease; LAD: left anterior descending; PRS: polygenic risk score; RCA: right coronary artery.
A 1-SD increase in PRSCHD was associated with higher percent stenosis in all coronary arteries (Table 2). The strongest associations were with RCA (β=8.6; 95% CI, 7.7 to 9.4; P=4×10−81) and LAD (β=7.4; 6.7 to 8.2; P=7×10−79). A 1-SD increase in PRSCHD was associated with an increase of 0.31 (95% CI, 0.28 to 0.33; P=4×10−144) in the log Gensini score. We observed a positive correlation between quintiles of PRSCHD and percent stenosis in each artery, as well as the number of stenotic and severely stenotic arteries (Figure 1).
Figure 1.
Distributions of percent stenosis and PRSCHD. A) Distributions of percent stenosis in coronary arteries and the Gensini score, stratified by PRSCHD quintiles. B) Distributions of PRSCHD stratified by the number of stenotic arteries (upper) and severely stenotic arteries (lower).
We compared the performance of PRSCHD to an older PRS for CHD developed in people of European ancestry (PRSKhera-2018, PGS000013)7. A 1-SD increase in PRSKhera-2018 was associated with a 0.25 (95% CI, 0.22 to 0.28; P=1×10−74) increase in log Gensini score. A model including PRSKhera-2018 and basic covariates (age, sex, cohort, five genetic PCs) explained 15.6% of the variance in the log Gensini score, whereas the basic covariate model explained 10.8% of the variance. In contrast, a model including PRSCHD explained 18.1% of the variance, highlighting that PRS for CHD developed on larger and more diverse GWAS summary statistics are more robustly associated with CHD.
Further adjustments for clinical risk factors for CHD (hypertension, LDL-C, type 2 diabetes, smoking status, and statin use) minimally changed the estimates for the associations between PRSCHD and the CAD severity measures (Table S1). All clinical risk factors were associated with the log Gensini score in a regression model that included PRSCHD and basic covariates (P<0.001). Adding PRSCHD and clinical risk factors to a basic covariate model added 0.107 to the R2 (Table S1). In comparison, adding only PRSCHD or only the clinical risk factors added 0.073 and 0.044 to the R2, respectively.
Associations of rare variants with CAD severity
We assessed whether carrying a P/LP variant in familial hypercholesterolemia (FH) genes (LDLR, APOB, or PCSK9) was associated with CAD severity after adjustment for PRSCHD (Supplemental Material). We observed 55 variants (MAF≤1%) in our cohort: 5 predicted loss-of-function (pLoF) and 42 missense variants in LDLR; one pLoF and three missense variants in APOB; and four missense variants in PCSK9 (Table S2). We assessed the associations between FH variant carrier status and the CAD severity measures in regression models that also included PRSCHD. Carrying an FH variant was associated with a higher log Gensini score (133 carriers; β=0.21; 95% CI, 0.03 to 0.38, P=0.021) but not with the dichotomous traits (Table S3).
We further binned patients into three groups depending on their PRSCHD; low PRSCHD (bottom quintile), intermediate PRSCHD (middle three quintiles), and high PRSCHD. We stratified on FH carrier status and used non-carriers with intermediate PRSCHD as the reference group. Among both carriers and non-carriers, there was a gradient in point estimates for the association with CAD severity traits depending on the PRSCHD group (Figure 2). The association estimates for carriers with low or intermediate PRSCHD were not significantly different from the reference group, but carriers with high PRSCHD had higher odds of 3-vessel disease (OR=3.72; 95% CI, 1.69 to 8.2; P=0.001) and log Gensini score (β=0.50; 0.12 to 0.88; P=0.01). Compared to the reference group, carriers had higher point estimates than non-carriers within each PRSCHD group for severe stenosis, 3-vessel disease, and the log Gensini score. However, we did not observe a significant interaction between PRSCHD and FH carrier status when an interaction term was included in these models (Table S4).
Figure 2.
Association between PRSCHD strata and CAD severity measures. We grouped patients into three groups of PRSCHD: low (first quintile), intermediate (middle three quintiles), and high (fifth quintile). We stratified by P/LP FH variant carrier status. We adjusted for age, sex, cohort, and five genetic PCs in all models. We treated non-carriers with intermediate PRSCHD as the reference group.
Stenosis severity mediates the associations of PRSCHD with prevalent CHD and incident MI
PRSCHD was associated with a clinical CHD diagnosis at first angiography (OR=1.43; 95% CI, 1.35 to 1.51; P=1×10−36). 1,264 patients (21%) had MI ≥3 months after their first coronary angiogram. PRSCHD was associated with incident MI over a mean follow-up of 9.2 years (HR=1.20; 95% CI, 1.13 to 1.27; P=5×10−10). When we excluded 577 patients with MI events before or within one month of the first angiography, the association was similar (HR=1.18; 95% CI, 1.11 to 1.26; P=2×10−7).
To explore whether CAD severity mediated the associations of PRSCHD with prevalent CHD and incident MI, we decomposed the total effect of PRSCHD into a direct and an indirect (mediated) effect, treating percent stenosis and the Gensini score as mediator variables in regression models and adjusting for basic covariates (Table 3). The mediated effects of all CAD severity measures were significant for prevalent CHD. The maximum stenosis in coronary arteries and the Gensini score conferred the largest effects: 61% and 60%, respectively. All mediated effects, but not all direct effects, were significant for incident MI. CAD severity mediated greater proportions of the total effect of PRSCHD on incident MI (90%, Gensini score) than prevalent CHD. We observed minimal changes in the regression estimates after additional adjustment for clinical risk factors (Table S5). Finally, we estimated to what extent the clinical risk factors mediated the associations of PRSCHD with CHD and MI, but observed lower proportions for all mediators (≤10%, Table S6).
Table 3.
Results of mediation analyses of prevalent CHD and incident MI.
| Mediator | Total effect (95% CI) | Direct effect (95% CI) | Indirect effect (95% CI) | Proportion mediated (95% CI) |
|---|---|---|---|---|
|
Clinical CHD diagnosis at first angiography | ||||
| Left main coronary artery | 0.086 (0.074–0.098) | 0.075 (0.063–0.086) | 0.012 (0.009–0.014) | 0.13 (0.10–0.17) |
| LAD | 0.083 (0.071–0.094) | 0.049 (0.036–0.060) | 0.034 (0.030–0.039) | 0.41 (0.35–0.49) |
| Circumflex | 0.085 (0.073–0.096) | 0.064 (0.052–0.075) | 0.021 (0.018–0.025) | 0.25 (0.20–0.31) |
| RCA | 0.084 (0.072–0.095) | 0.054 (0.042–0.065) | 0.030 (0.026–0.034) | 0.35 (0.30–0.42) |
| All arteries (max. value) | 0.082 (0.070–0.093) | 0.032 (0.020–0.043) | 0.050 (0.045–0.055) | 0.61 (0.53–0.72) |
| Gensini score | 0.084 (0.072–0.095) | 0.034 (0.023–0.046) | 0.050 (0.045–0.055) | 0.60 (0.51–0.69) |
|
Incident MI ≥3 months after first angiography | ||||
| Left main coronary artery | 0.038 (0.026–0.049) | 0.028 (0.016–0.039) | 0.010 (0.008–0.012) | 0.26 (0.18–0.39) |
| LAD | 0.039 (0.027–0.051) | 0.017 (0.005–0.029) | 0.022 (0.019–0.026) | 0.57 (0.43–0.81) |
| Circumflex | 0.038 (0.027–0.049) | 0.021 (0.011–0.033) | 0.016 (0.014–0.019) | 0.44 (0.32–0.61) |
| RCA | 0.039 (0.028–0.049) | 0.015 (0.004–0.027) | 0.023 (0.020–0.027) | 0.60 (0.45–0.86) |
| All arteries (max. value) | 0.041 (0.031–0.053) | 0.008 (−0.003–0.018) | 0.034 (0.030–0.038) | 0.82 (0.64–1.10) |
| Gensini score (log scale) | 0.039 (0.028–0.050) | 0.004 (−0.007–0.015) | 0.035 (0.031–0.039) | 0.90 (0.70–1.20) |
We used PRSCHD as the independent variable and percent stenosis in coronary arteries and the Gensini score as mediator variables.
CHD: coronary heart disease; LAD: left anterior descending; MI: myocardial infarction; RCA: right coronary artery.
Discussion
A PRSCHD derived from multi-ancestry GWAS summary statistics of CAD (PGS003726)9 was associated with multiple measures of CAD severity, including the log Gensini score. Carrying a P/LP variant in a FH gene (LDLR, APOB, or PCSK9) was associated with a higher log Gensini score after adjustment for PRSCHD. PRSCHD was associated with incident MI events, and this association was mediated to a large extent by CAD severity.
In a previous study of patients with angiographic CAD, those in the fifth PRSCHD quintile had 1.7 times higher odds of multivessel CAD than those in the first quintile14. In a study of patients with premature acute coronary syndrome, a PRSCHD above the median was associated with 1.4-fold higher odds of multivessel disease15. However, these studies were limited to PRSCHD of ≤50 SNPs and did not analyze global measures for CAD severity, such as the Gensini score. A more recent study of 1,645 patients with CAD demonstrated associations of a larger PRSCHD with an increased overall burden of CAD, quantified by coronary artery calcium and segment stenosis scores, and showed that the association of PRSCHD with increased CAD burden was not specific to plaque characteristics17. Our findings support and extend those of previous studies and suggest that a higher PRSCHD is associated with the presence of more severe CAD, across the three major epicardial coronary arteries and in patients with or without a clinical ASCVD diagnosis at the time of angiography. Furthermore, we showed that a recent multi-ancestry PRSCHD explained more variance in the log Gensini score (improvement in R2: 0.073) than a previous European-ancestry PGSKhera-2018 (improvement in R2: 0.048).
We tested for associations between P/LP variants in FH genes and CAD severity measures. Although carrying a P/LP variant in FH genes was associated with a higher log Gensini score, it was not associated with the dichotomous CAD severity traits. We note that our cohort consisted of relatively older patients referred for angiography (mean age, 70 years), so the effect of these variants may be underestimated. Previously, Fahed et al. demonstrated that polygenic “background” modifies the effect of FH variants on CHD risk in the UK Biobank, a relatively younger and healthier cohort18. We extended these analyses to other CAD severity measures but observed less contrast between FH carriers and non-carriers based on polygenic background, possibly due to the nature of our cohort.
Differential associations have been observed between common genetic variants and coronary atherosclerotic burden and adverse CHD events. Reilly et al.12 demonstrated that sequence variants at the ABO locus contributed to MI risk in the presence of coronary atherosclerosis but not to coronary atherosclerosis itself, suggesting that some variants increase MI risk through other mechanism than plaque formation. A subsequent large GWAS of MI highlighted loci that are more strongly associated with MI than CAD, and MI in the presence of CAD, but also demonstrated that most MI-associated loci are also associated with CAD19. Analyses of genetic correlations between the two phenotypes have further provided evidence of their shared genetic basis20. In our analyses, PRSCHD was associated with incident MI, and this association was mediated to a large extent by CAD severity, indicating that the genetic basis, as captured by PRSCHD, of CAD severity and adverse CHD events, such as MI, considerably overlap.
The main strength of our study was our cohort of participants with coronary angiography, genotyping, and exome sequencing data, enabling a comprehensive assessment of the associations of both PRSCHD and rare FH variants with measures of CAD severity. A cardiologist ascertained angiographic severity for clinical reporting. Several limitations of our study need to be mentioned. First, our cohort was relatively old and enriched in CHD cases. Second, the association of PRSCHD with incident MI was weaker than with prevalent CHD at the time of first angiography. This difference may be explained by index event bias21, as the majority of participants had CHD at baseline. Third, our analyses were restricted to individuals of European ancestry, limiting generalizability to other populations.
In conclusion, a PRSCHD was robustly associated with CAD severity and the risk of incident MI after the first angiography. P/LP variants in FH genes were associated with a higher log Gensini score after adjustment for PRSCHD. The association between PRSCHD and MI was mediated to a large extent by CAD severity, suggesting a considerable overlap in the genetic basis, as captured by PRSCHD, of CAD severity and MI.
Supplementary Material
Acknowledgments:
We acknowledge Regeneron Genetics Center for providing genetic data for the participants in the study. Project Generation was partly supported by Mayo Clinic’s Center for Individualized Medicine. We thank all the participants from the Mayo Clinic Biobank and Mayo Vascular Disease Biorepository.
Sources of Funding:
This study was funded by grants U01 HG006379 and U01HG011710 from the National Human Genome Research Institute and K24 HL137010 from the National Heart Lung and Blood Institute.
Non-standard Abbreviations and Acronyms
- ASCVD
atherosclerotic cardiovascular disease
- CAD
coronary artery disease
- CHD
coronary heart disease
- FH
familial hypercholesterolemia
- MCB
Mayo Clinic Biobank
- MI
myocardial infarction
- PRS
polygenic risk score
- VDB
Vascular Disease Biorepository
Footnotes
Disclosures: None
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