Demographic and clinical characteristics of the study population
Among the 3,139 patients included in this study, there were 2,334 males (74.4%) and 805 females (25.6%). When CAD was initially diagnosed, the median age was 64 years (IQR: 56, 71 years). During the follow-up period, 574 major cardiovascular events occurred, including 396 cardiovascular events, 173 stroke events, and 263 CAD. 234 patients died during the follow-up, 119 of which were due to cardiovascular diseases. Table 1 displays the detailed demographic and clinical characteristics of the study participants.
Table 1
Demographic and clinical characteristics of the study population in the cohort study
Characteristics | Group | CAD cases* | CVD incidence | Stroke incidence | CAD recurrence | CVD death | All cause death | MACEs incidence |
| | (n = 3139) | (n = 396) | (n = 173) | (n = 263) | (n = 119) | (n = 234) | (n = 574) |
Age (year) | | 64.17 (55.50, 71.01) | 66.15 (58.12, 72.74) | 67.32 (59.85, 73.41) | 65.65 (57.52, 72.49) | 71.65 (66.09, 76.69) | 71.06 (65.15, 75.92) | 67.71 (60.64, 73.82) |
Gender [n (%)] | Male | 2334 (74.4) | 292 (73.7) | 120 (69.4) | 201 (76.4) | 79 (66.4) | 162 (69.2) | 413 (72.0) |
| Female | 805 (25.6) | 104 (26.3) | 53 (30.6) | 62 (23.6) | 40 (33.6) | 72 (30.8) | 161 (28.0) |
SBP (mmHg) | | 130 (120, 146) | 132 (120, 147) | 136 (122, 150) | 130 (120, 144) | 126 (109, 138) | 130 (117, 144) | 131 (120, 146) |
DBP (mmHg) | | 80 (71, 87) | 80 (71, 86) | 80 (71, 87) | 79 (70, 84) | 75 (68, 80) | 76 (69, 84) | 78 (70, 84) |
GLU (mmol/L) | | 5.43 (4.71, 7.03) | 5.46 (4.71, 7.20) | 5.38 (4.66, 6.78) | 5.51 (4.76, 7.32) | 5.53 (4.69, 7.98) | 5.53 (4.68, 7.72) | 5.52 (4.72, 7.56) |
TC (mmol/L) | | 4.29 (3.58, 5.02) | 4.22 (3.46, 5.03) | 4.26 (3.43, 5.08) | 4.23 (3.48, 4.96) | 4.15 (3.63, 5.36) | 4.21 (3.64, 5.06) | 4.24 (3.53, 5.04) |
TG (mmol/L) | | 1.43 (1.01, 2.1) | 1.48 (1.01, 2.09) | 1.51 (1.01, 2.09) | 1.48 (1.01, 2.12) | 1.31 (0.94, 1.8) | 1.3 (0.93, 1.79) | 1.4 (0.99, 1.98) |
HDL-C (mmol/L) | | 1.05 (0.92, 1.22) | 1.04 (0.92, 1.19) | 1.03 (0.90, 1.21) | 1.05 (0.92, 1.17) | 1.09 (0.97, 1.31) | 1.09 (0.96, 1.27) | 1.06 (0.93, 1.21) |
LDL-C (mmol/L) | | 2.51 (1.97, 3.07) | 2.41 (1.91, 3.02) | 2.48 (1.87, 3.12) | 2.38 (1.91, 2.97) | 2.44 (1.98, 3.14) | 2.45 (1.98, 3.00) | 2.45 (1.92, 3.04) |
Smoking [n (%)] | No | 1819 (57.9) | 245 (61.9) | 112 (64.7) | 158 (60.1) | 79 (66.4) | 157 (67.1) | 366 (63.8) |
| Yes | 1320 (42.1) | 151 (38.1) | 61 (35.3) | 105 (39.9) | 40 (33.6) | 77 (32.9) | 208 (36.2) |
Drinking [n (%)] | No | 2644 (84.2) | 351 (88.6) | 155 (89.6) | 233 (88.6) | 107 (89.9) | 203 (86.8) | 506 (88.2) |
| Yes | 495 (15.8) | 45 (11.4) | 18 (10.4) | 30 (11.4) | 12 (10.1) | 31 (13.2) | 68 (11.8) |
Hypertension[n (%)] | No | 1050 (33.5) | 108 (27.3) | 43 (24.9) | 72 (27.4) | 39 (32.8) | 72 (30.8) | 163 (28.4) |
| Yes | 2089 (66.5) | 288 (72.7) | 130 (75.1) | 191 (72.6) | 80 (67.2) | 162 (69.2) | 411 (71.6) |
Diabetes [n (%)] | No | 2156 (68.7) | 252 (63.6) | 103 (59.5) | 172 (65.4) | 82 (68.9) | 161 (68.8) | 372 (64.8) |
| Yes | 983 (31.3) | 144 (36.4) | 70 (40.5) | 91 (34.6) | 37 (31.1) | 73 (31.2) | 202 (35.2) |
Dyslipidemia[n (%)] | No | 1515 (48.3) | 191 (48.2) | 84 (48.6) | 129 (49.0) | 67 (56.3) | 135 (57.7) | 296 (51.6) |
| Yes | 1624 (51.7) | 205 (51.8) | 89 (51.4) | 134 (51.0) | 52 (43.7) | 99 (42.3) | 278 (48.4) |
* CAD cases aged between 35 and 80 years were selected. |
Presented as Median and Interquartile range (IQR), total numbers or percentages in brackets. |
MACEs, major adverse cardiovascular events; CVD, cardiovascular disease; CAD, coronary artery disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; GLU, glucose; TC, total cholesterol;TG, triglyceride; HDL-C,high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol. |
Association analysis of single loci and MACEs
The genotype frequency distribution of 10 SNPs, except for rs13053714, rs6845322, and rs246390, were found to be consistent with Hardy-Weinberg equilibrium (P > 0.05). The genotype and allele frequencies of all SNPs in patients are reported in Supplementary Table 1, and important genetic parameters related to these SNPs can be found in Supplementary Table 2.
The genetic variation of rs246390 A > G at PDGFRB was associated with an increased risk of MACEs and CVD (Fig. 2), and adjusted HRs (95% CIs) of the additive model were 1.171 (1.034, 1.325) and 1.174 (1.011, 1.362) with P values of 0.011 and 0.036, respectively (Supplementary Table 3 and Supplementary Table 4). After FDR correction the associations were not anymore statistically significant (all P > 0.05).
Association between wGRS stratification and MACEs
According to the multivariate Cox regression analysis, the wGRSs of MACEs incidence, CVD incidence, stroke incidence, CAD recurrence, CVD death, and all cause death were generated based on the number and weight of effective alleles of 13 SNPs and further devided into low risk (Q1), medium risk (Q2 ~ Q4) and high risk (Q5) from quintiles (Supplementary Table 4). For the outcome of MACEs incidence, individuals with high wGRSMACE had a higher risk compared to those with low wGRSMACE, with adjusted HR (95% CI) of 1.441 (1.108, 1.875) (P = 0.006). In addition, for the incidence of CVD, the adjusted HRs (95% CIs) of high wGRSCVD and medium wGRSCVD were 1.755(1.270, 2.426) (P = 0.001) and 1.386 (1.044, 1.840) (P = 0.024) compared to those with low GRS.
Similarly, compared to those with low wGRSCAD, individuals with high wGRSCAD and medium wGRSCAD exhibited an increased risk of CAD recurrence with adjusted HRs (95% CIs) of 1.990 (1.325, 2.988) (P = 0.001) and 1.523 (1.061, 2.187) (P = 0.023), respectively. Additionally, individuals with high wGRS had higher risks of CVD-related and all-cause death in comparison to those with low wGRS and the adjusted HRs (95% CIs) were 1.868 (1.039, 3.358) and 1.604 (1.053, 2.443), with P values of 0.028 and 0.037, respectively (Fig. 3).
Discrimination performance of the MACE prediction model
Compared with the TRFs model, adding wGRSMACE increased the C-index for predicting post-CAD MACEs by 0.415% (P = 0.396). When wGRSMACE was combined with TRFs and GRACE score, the integrated model had a C-index of 0.624, with an improvement of 0.425% from wGRS (P = 0.403). Additionally, combining wGRS with TRFs and/or GRACE score slightly improved the predictive value for CVD incidence, stroke incidence, CAD recurrence, CVD mortality, and all-cause death in comparison to TRFs mode; however, these improvements were not statistically significant (all P > 0.05).
Discrimination improvement of adding wGRS to traditional and clinical models
Compared to the TRFs prediction model, we found that the addition of wGRSMACE, wGRSCVD, and wGRSCAD contributed to an improvement in NRI of 5.1% (95% CI, 0.7–9.5%, P < 0.001), 6.3% (95% CI, 0.5–11.4%, P < 0.001), and 12.0% (95% CI, 2.5–18.3%, P < 0.001), respectively. Regarding the overall predictive ability of models, adding wGRS slightly improved the TRFs prediction model for MACEs, CVD, stroke incidence, and CAD recurrence, with IDIs of 0.3% (95% CI, 0.0–0.6%, P < 0.001), 0.4% (95%CI, 0.0–0.5%, P < 0.001), 0.1% (95%CI, 0.0–0.3%, P < 0.001), and 0.4% (95%CI, 0.0–0.9%, P < 0.001), respectively.
Additionally, compared to the TRFs and GRACE score model, the addition of wGRSMACE, wGRSCVD, and wGRSCAD contributed to an improvement in NRI of 5.1% (95% CI, 0.7–9.6%, P < 0.001), 6.5% (95% CI, 0.1–10.7%, P < 0.001), and 12.8% (95% CI, 0.4–18.5%, P < 0.001), respectively. Furthermore, adding wGRS slightly improved the integrated discrimination of the TRFs and GRACE model for predicting MACEs, CVD, CAD recurrence, and CVD death, with an IDI of 0.3% (95% CI, 0.0–0.5%, P < 0.001), 0.4% (95% CI, 0.0–0.7%, P < 0.001), 0.4% (95% CI, 0.1–0.9%, P < 0.001), and 0.2% (95% CI, 0.0–0.8%, P < 0.001), respectively (Table 2).
Table 2
MACEs and its individual components discrimination using Harrel’s C-statistic, NRI and IDI
Outcome | Models | | C | | | NRI | | IDI |
C (95% CI) | Change (%) | P value | | NRI (95% CI) | P value | | IDI (95% CI) | P value |
MACEs incidence | GRS + TRFs + GRACE | 0.624(0.604,0.652) | 0.425%a | 0.403a | | 5.1%(0.7%,9.6%) | <0.001 | | 0.3%(0.0%,0.5%] | <0.001 |
| GRS + TRFs | 0.617(0.597,0.645) | 0.415%b | 0.396b | | 5.1%(0.7%,9.5%) | <0.001 | | 0.3%(0.0%,0.6%] | <0.001 |
| TRFs + GRACE | 0.619(0.600,0.647) | | | | | | | | |
| TRFs | 0.613(0.583,0.640) | | | | | | | | |
| GRS | 0.535(0.511,0.560) | | | | | | | | |
CVD incidence | GRS + TRFs + GRACE | 0.597(0.578,0.634) | 0.863%a | 0.270a | | 6.5%(0.1%,10.7%) | <0.001 | | 0.4%(0.0%,0.7%] | <0.001 |
| GRS + TRFs | 0.597(0.576,0.632) | 0.931%b | 0.251b | | 6.3%(0.5%,11.4%) | <0.001 | | 0.4%(0.0%,0.5%] | <0.001 |
| TRFs + GRACE | 0.589(0.569,0.624) | | | | | | | | |
| TRFs | 0.587(0.567,0.622) | | | | | | | | |
| GRS | 0.546(0.516,0.576) | | | | | | | | |
Stroke incidence | GRS + TRFs + GRACE | 0.637(0.608,0.692) | 0.545%a | 0.228a | | 1.9%(-1.5%,10.3%) | 0.182 | | 0.1%(-0.1%,0.4%) | 0.364 |
| GRS + TRFs | 0.630(0.599,0.683) | 0.400%b | 0.360b | | 3.1%(-4.9%,8.8%) | 0.727 | | 0.1%(0.0%,0.3%] | <0.001 |
| TRFs + GRACE | 0.632(0.602,0.685) | | | | | | | | |
| TRFs | 0.626(0.595,0.678) | | | | | | | | |
| GRS | 0.535(0.495,0.581) | | | | | | | | |
CAD recurrence | GRS + TRFs + GRACE | 0.600(0.580,0.645) | 1.713%a | 0.128a | | 12.8%(0.4%,18.5%) | <0.001 | | 0.4%(0.1%,0.9%) | <0.001 |
| GRS + TRFs | 0.600(0.579,0.644) | 1.701%b | 0.118b | | 12.0%(2.5%,18.3%) | <0.001 | | 0.4%(0.0%,0.9%] | <0.001 |
| TRFs + GRACE | 0.583(0.565,0.628) | | | | | | | | |
| TRFs | 0.584(0.562,0.626) | | | | | | | | |
| GRS | 0.556(0.522,0.592) | | | | | | | | |
CVD death | GRS + TRFs + GRACE | 0.750(0.710,0.800) | 1.586%a | 0.161a | | 4.1%(-1.1%,13.3%) | 0.182 | | 0.2%(0.0%,0.8%] | <0.001 |
| GRS + TRFs | 0.716(0.674,0.770) | 1.284%b | 0.254b | | 6.6%(-2.3%,12.4%) | 0.364 | | 0.2%(-0.1%,0.5%) | 0.182 |
| TRFs + GRACE | 0.735(0.693,0.787) | | | | | | | | |
| TRFs | 0.703(0.661,0.757) | | | | | | | | |
| GRS | 0.574(0.519,0.628) | | | | | | | | |
All cause death | GRS + TRFs + GRACE | 0.728(0.698,0.765) | 0.501%a | 0.357a | | 2.2%(-6.7%,8.3%) | 0.545 | | 0.0%(-0.2%,0.2%) | 0.909 |
| GRS + TRFs | 0.697(0.668,0.736) | 0.341%b | 0.531b | | 2.6%(-6.6%,9.0%) | 0.545 | | 0.1%(-0.1%,0.3%) | 0.909 |
| TRFs + GRACE | 0.723(0.692,0.759) | | | | | | | | |
| TRFs | 0.693(0.663,0.730) | | | | | | | | |
| GRS | 0.543(0.505,0.582) | | | | | | | | |
a comparison between GRS + TRFs + GRACE and TRFs + GRACE models; b comparison between GRS + TRFs and TRFs models. |
Harrel’s C-statistic confidence intervals were calculated using the bootstrap method, and the p-value was determined using Z testing. The NRI and IDI were calculated using the survIDINRI package in R. Confidence intervals were computed using the bootstrap method, and p-values were determined by comparing the log-rank statistics of the baseline and updated models. |
MACEs, major adverse cardiovascular events; GRACE, global registry of acute coronary events; CVD, cardiovascular disease; CAD, coronary artery disease;TRFs,traditional risk factors; GRS, genetic risk score; CI, Confidence interval; NRI, net reclassification index; IDI, integrated discrimination index. |
Discrimination of the MACE prediction model by AUC values
Compared with the TRFs model, adding wGRSMACE increased the AUC for predicting post-CAD MACE by 0.639% (P = 0.338). When wGRSMACE was combined with TRFs and GRACE score, the integrated model had an AUC of 0.632, with an improvement of 0.637% in comparison with the TRFs and GRACE score model (P = 0.308).
Based on the results, the wGRSCVD+TRFs + GRACE model exhibited an incremental predictive value for CVD mortality outcome in comparison to the TRFs + GRACE model, with AUC (95% CI) of 0.751 (0.705,0.797) (P = 0.032). Compared with the TRFs model, the wGRSCVD+TRFs model resulted in a 1.683% increase in AUC, while the P value of DeLong test was 0.124 (Supplementary Table S5).
Association analysis of coronary artery lesion counts with MACE and CVD in different GRS stratification
In the low wGRSMACE group, CAD patients with single vessel lesions exhibited a significantly increased risk of MACEs in comparison to those without vessel lesions and the adjusted HR (95%CI) was 2.406 (1.102, 5.251) (P = 0.028). Besides, patients diagnosed with dual, triple, or single to triple vessel lesions demonstrated a significantly higher risk of MACEs in the medium wGRSMACE group compared to those with no vessel lesion and low wGRSMACE levels, and the adjusted HRs (95%CIs) were 2.844 (1.855, 4.361) (P < 0.001), 2.553 (1.720, 3.790) (P < 0.001), and 2.123 (1.502, 3.000) (P < 0.001), respectively. Similarly, patients with the high wGRSMACE level and no, dual, triple, or single to triple lesions had a significant increased risk of MACEs in comparison to those with no vessel lesions and the low wGRSMACE levels, with adjusted HRs (95%CIs) of 1.499 (1.119, 2.009) (P = 0.007), 2.390 (1.148, 4.976) (P = 0.020), 2.448 (1.351, 4.436) (P = 0.003) and 1.882 (1.140, 3.106) (P = 0.013), respectively.
In the low wGRSCVD group, CAD patients with single vessel lesions exhibited a significantly increased risk of CVD incidence in comparison to those without vessel lesions and the adjusted HR (95%CI) was 3.000 (1.181, 7.619) (P = 0.021). As for the medium wGRSCVD group, patients with single, dual, triple, and single to triple vessel lesion had a significantly increased incidence of CVD in comparison to patients with no vessel lesion in low wGRSCVD group, and the adjusted HR (95%CI) were 2.452 (1.316, 4.568) (P = 0.005), 3.248 (1.904, 5.538) (P < 0.001), 2.820 (1.708, 4.655) (P < 0.001) and 2.427 (1.567, 3.760) (P < 0.001), respectively. Furthermore, compared to the lowest wGRSCVD group without vessel lesions, there was a significant increase in the risk of post-CAD CVD incidence in the high wGRSCVD group with no, dual, triple, or single to triple vessel lesion, with the adjusted HRs (95%CI) of 3.480 (1.634, 7.413) (P = 0.001), 3.700 (1.904, 7.188) (P < 0.001) and 2.724 (1.552, 4.781) (P < 0.001), respectively (Fig. 4 and Supplementary Table S6).
Correlation between wGRS and GRACE score, and clinical indices
MPV had weak positive correlations with wGRSstroke and wGRSCAD, and a weak negative correlation with wGRSCVDdeath after CAD (all | r | < 0.1, P < 0.05). Besides, PDW had weak negative correlations with wGRSMACE and wGRSCVD (| r | < 0.1, P < 0.05). Furthermore, epidermal growth factor receptor (eGFR) had weak negative correlations with wGRSCVD_death and wGRSACD (| r | < 0.1, P < 0.05) after CAD. No statistical correlation was found between wGRS and metabolic indices including glucose, blood pressure, lipids, and other platelet parameters (P > 0.05) among the CAD patients (Supplementary Fig. 1).
In patients with CAD, weak positive correlations were observed between the GRACE score and wGRSMACE and wGRSCVD (| r | < 0.1, P < 0.05) as shown in Supplementary Table S6. Additionally, among AMI patients, the GRACE score showed positive correlations with wGRSMACE, wGRSCVD, wGRSstroke, and wGRSCAD (all | r | < 0.1, P < 0.05) (Supplementary Table S7). Moreover, for ST-segment elevation myocardial infarction (NSTEMI) patients, the GRACE score exhibited positive correlations with wGRSMACE (r = 0.154, P = 0.005), wGRSCVD (r = 0.153, P = 0.005), wGRSstroke (r = 0.139, P = 0.011), wGRSCAD (r = 0.141, P = 0.010), and wGRSACD (r = 0.119, P = 0.030) (Supplementary Table S8). However, further subgroup analysis based on AP patients into stable angina (SA), unstable angina (UA), and angina pectoris-unspecified etiology (AP_UE) groups did not reveal any statistically significant correlations (Supplementary Table S9).