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From March 2011 to March 2013, 1, 024 patients who underwent PCI and received post intervention aspirin and clopidogrel, were enrolled in the study. All these patients also completed platelet function measures and genetic sampling tests. The minor allele frequencies of the ADRA2A SNPs (rs11195419, rs3750625, rs553668, and rs13306146) and CYP2C19*2 (rs4244285) were 18.1%, 17.2%, 43.7%, 25.4%, and 32.1%, respectively. The homozygous groups of the SNPs were 2.7%, 2.7%, 19.5%, 8.0%, and 10.4%, respectively. Genotypic distributions of these SNPs conformed with the Hardy-Weinberg equilibrium. The allele and genotype frequencies are reported in Table 1. The average age of the patients was 58.5 ± 10.5 years, and > 75% were males. Less than half of the patients presented with ACS (31.8%). PCIs were mostly performed using drug-eluting stents (99.2%). History of diabetes was significantly different across rs11195419 (P = 0.023) and rs3750625 (P = 0.023) genotypes. Platelets count (P = 0.019), current smoking history (P = 0.048), and previous myocardial infarction history (P = 0.049) were also significantly different across the rs553668 genotypes. The baseline characteristics of SNPs (rs11195419 and rs3750625) are presented in Table 2 and the SNPs (rs553668 and rs13306146) are reported in the Appendix (available in www. besjournal.com).
Characteristics RS11195419 N (%) RS3750625 N (%) RS553668 N (%) RS13306146 N (%) Allele frequency, n = 2, 048 Major allele 1, 677 (81.9) 1, 695 (82.8) 1, 160 (56.6) 1, 528 (74.6) Minor allele 371 (18.1) 353 (17.2) 888 (43.4) 520 (25.4) Genotype frequency, n = 1, 024 Wild type 682 (66.6) 700 (68.4) 334 (32.6) 587 (57.3) Heterozygote 313 (30.6) 295 (28.8) 492 (48.0) 354 (34.6) Homozygote 29 (2.8) 29 (2.8) 198 (19.3) 83 (8.1) Table 1. Allele and Genotype Frequency of ADRA2A Genetic Variants
Variables RS11195419 RS3750625 WT
(N = 682)HE
(N = 313)HO
(N = 29)P WT
(N = 700)HE
(N = 295)HO
(N = 29)P Age, years 58.2 ± 10.6 59.2 ± 11.6 59.0 ± 7.6 0.692 58.2 ± 10.6 59.2 ± 10.6 59.8 ± 8.2 0.273 Male, n (%) 525 (77.0) 227 (72.5) 21 (72.4) 0.293 537 (76.7) 216 (73.2) 20 (69.0) 0.358 BMI, kg/m2 26.0 ± 3.2 26.2 ± 3.2 25.8 ± 3.7 0.739 26.0 ± 3.2 26.2 ± 3.3 26.0 ± 3.7 0.531 Platelet, × 109/L 206.4 ± 53.3 204.3 ± 56.7 183.8 ± 55.4 0.089 207.0 ± 53.5 202.2 ± 56.0 189.2 ± 61.1 0.126 ACS, n (%) 228 (33.4) 92 (29.4) 6 (20.7) 0.190 232 (32.1) 88 (29.8) 6 (20.7) 0.252 DM, n (%) 186 (27.3) 110 (35.1) 12 (41.4) 0.017 192 (27.4) 104 (35.3) 12 (41.4) 0.020 Hypertension, n (%) 425 (62.3) 192 (61.3) 16 (55.2) 0.725 436 (62.3) 180 (61.0) 17 (58.6) 0.873 HCL, n (%) 573 (84.0) 270 (86.3) 22 (75.9) 0.285 589 (84.1) 254 (86.1) 22 (75.9) 0.318 Current smoking, n (%) 261 (38.3) 114 (36.4) 8 (27.6) 0.463 267 (38.1) 109 (36.9) 7 (24.1) 0.306 CHD family history, n (%) 7 (1.0) 4 (1.3) 1 (3.4) 0.484 7 (1.0) 4 (1.4) 1 (3.4) 0.458 Previous MI, n (%) 124 (18.2) 45 (14.4) 5 (17.2) 0.332 127 (18.1) 41 (13.9) 6 (20.7) 0.230 Previous PCI, n (%) 103 (15.1) 39 (12.5) 5 (17.2) 0.491 103 (14.7) 39 (13.2) 5 (17.2) 0.749 Previous CABG, n (%) 3 (0.4) 2 (0.6) 0 (0) 0.852 3 (0.4) 2 (0.7) 0 (0) 0.814 LAD, n (%) 379 (55.6) 192 (61.3) 20 (69.0) 0.107 386 (55.1) 185 (62.7) 20 (69.0) 0.040 LCX, n (%) 197 (28.9) 90 (28.8) 7 (24.1) 0.858 204 (29.1) 82 (27.8) 8 (27.6) 0.904 RCA, n (%) 314 (46.0) 141 (45.0) 11 (37.9) 0.678 322 (46.0) 133 (45.1) 11 (37.9) 0.684 LM, n (%) 31 (4.5) 19 (6.1) 0 (0) 0.272 32 (4.6) 18 (6.1) 0 (0) 0.275 Statin, n (%) 663 (97.2) 302 (96.5) 29 (100) 0.522 681 (97.3) 284 (96.3) 29 (100.0) 0.438 β-blocker, n (%) 604 (88.6) 278 (88.8) 27 (93.1) 0.750 621 (88.7) 261 (88.5) 27 (93.1) 0.750 ACEI/ARB, n (%) 408 (59.8) 183 (58.5) 13 (44.8) 0.268 418 (59.7) 173 (58.6) 13 (44.8) 0.277 CCB, n (%) 256 (37.5) 129 (41.2) 8 (27.6) 0.260 264 (37.7) 121 (41.0) 8 (27.6) 0.297 PPIs, n (%) 115 (16.9) 43 (13.7) 4 (13.8) 0.435 120 (17.1) 38 (12.9) 4 (13.8) 0.232 DES, n (%) 676 (99.1) 311 (99.4) 29 (100) 0.821 694 (99.1) 293 (99.3) 29 (100.0) 0.852 BMS, n (%) 5 (0.7) 1 (0.3) 0 (0) 0.668 5 (0.7) 1 (0.3) 0 (0) 0.713 Ballooning only, n (%) 1 (0.1) 1 (0.3) 0 (0) 0.824 1 (0.1) 1 (0.3) 0 (0) 0.791 Note. WT: Wild Type, HE: Heterozygote, HO: Homozygote, ADRA2A: the α2A-adrenergic receptor gene, BMI: body mass index, ACS: acute coronary syndrome, DM: diabetes mellitus, CHD: coronary heart disease, HCL: Hypercholesterolemia, MI: myocardial infarction, PCI: percutaneous coronary intervention, CABG: coronary artery bypass grafting, LAD:left anterior descendens, LCX: left circumflex, RCA: right coronary artery, ACEI: angiotensin conversion enzyme inhibitor, ARB: angiotensin receptor blocker, CCB: calcium channel blocker, PPI: proton pump inhibitor, DES: Drug-eluting stent, BMS: Bare mental stent. Table 2. Baseline Characteristics by ADRA2A Genotypes (rs11195419 and rs3750625)
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The median level of ADP inhibition was 52.7% ± 29.0%. ADP inhibition was significantly different among genotypes with rs11195419 (adjusted P = 0.022) and rs3750625 (adjusted P = 0.016) in additive model and the homozygous groups of these SNPs had the lowest ADP inhibition (39.3% ± 19.5% and 37.5% ± 18.6%, respectively). However, there we did not observe differences in ADP inhibition among genotypes with rs13306146 and rs553668. We did not identify any association with AA inhibition and ADRA2A SNPs either (Table 3). We also found the ADP inhibition was significantly different according to the CYP2C*2 genotype (P = 0.005). (The allele, genotypes and ADP inhibition of CYP2C19*2 are presented in Table 4). We conducted a multivariate analysis including CYP2C19*2 genotype and other potential confounders to identify whether the two significantly associated SNPs of ADRA2A by univariate analysis were independently related to ADP inhibition. The multivariate analysis indicated that rs11195419 (95% CI: -21.3 to -1.0; P = 0.033) and rs3750625 (95% CI: -22.3 to -2.0; P = 0.020) were independent predictors of ADP inhibition (Table 5). A significant association of ADP inhibition was also observed with CYP2C19*2, male, age and hypertension.
SNPs ADP Inhibition, % Additive Model P Value Additive Model Adjusted P Value AA Inhibition, % Additive Model P Value Additive Model Adjusted P Value Wild type Heterozygote Homozygote Wild type Heterozygote Homozygote RS11195419 54.2 ± 29.7 50.7 ± 27.7 39.3 ± 19.5 0.011 0.022 88.5 ± 20.0 89.3 ± 18.9 85.3 ± 20.7 0.351 1.404 RS3750625 54.0 ± 29.8 51.1 ± 27.4 37.5 ± 18.6 0.004 0.016 88.8 ± 19.3 88.8 ± 19.8 85.4 ± 20.7 0.356 0.712 RS13306146 51.8 ± 28.1 54.3 ± 30.3 52.1 ± 29.4 0.857 0.857 87.6 ± 21.0 90.0 ± 17.7 90.3 ± 18.1 0.428 0.571 RS553668 52.3 ± 30.1 54.4 ± 29.3 50.5 ± 27.7 0.812 1.083 87.6 ± 19.9 89.3 ± 20.0 88.9 ± 19.0 0.810 0.810 Note. SNP: single nucleotide polymorphism; ADP: adenosine diphosphate, AA: arachidonic acid. Table 3. Association of ADP Inhibition with ADRA2A Genotypes
Allele Frequency
(N = 2, 048)N (%) Genotype Frequency (N = 1, 024) N (%) ADP Inhibition , % P Value Major allele 1, 391 (67.9) Wild type 474 (46.3) Wild type 55.2 ± 28.7 Minor allele 657 (32.1) Heterozygote 443 (43.3) Heterozygote 51.7 ± 28.9 0.005 Homozygote 107 (10.4) Homozygote 45.5 ± 29.2 Note. ADP: adenosine diphosphate. Table 4. Allele, Geneotype Frequency and Association of ADP Inhibition with CYP2C19*2
Variables RS11195419 RS3750625 Univariate Analysis Multivariate Analysis Univariate Analysis Multivariate Analysis Coef (95% CI) P Coef (95% CI) P Coef (95% CI) P Coef (95% CI) P SNPs -2.5 (-24.5 to -3.1) 0.011 -2.1 (-21.3 to -1.0) 0.033 -2.5 (-24.5 to -3.1) 0.011 -2.3 (-22.3 to -2.0) 0.020 CYP2C19*2 -2.7 (-13.8 to -2.2) 0.007 -3.1 (14.3 to -3.3) 0.002 -2.7 (-13.8 to -2.2) 0.007 -3.1 (-14.3 to -3.3) 0.002 Male 6.8 (10.0 to -18.1) < 0.001 4.2 (5.1 to 13.9) < 0.001 6.8 (10.0 to -18.1) < 0.001 4.2 (5.0 to 13.9) < 0.001 Age (year) -4.4 (-0.5 to -0.2) < 0.001 -2.8 (-0.4 to -0.1) 0.005 -4.4 (-0.5 to -0.2) < 0.001 -2.8 (-0.4 to -0.1) 0.005 BMI (kg/m2) 2.3 (0.1 to 1.2) 0.018 2.0 (0.1 to 1.1) 0.047 2.3 (0.1 to 1.2) 0.018 2.0 (0.1 to 1.1) 0.043 Hypertension -2.8 (-8.8 to -1.5) 0.006 -2.0 (-8.0 to -0.1) 0.047 -2.8 (-8.8 to -1.5) 0.006 -2.0 (-7.9 to -0.2) 0.049 Hypercholesterolemia 2.10 (0.3 to 10.1) 0.036 2.0 (0.1 to 9.5) 0.044 2.10 (0.3 to 10.1) 0.036 2.0 (0.1 to 9.4) 0.045 Acute coronary syndrome 4.5 (5.03 to 12.9) < 0.001 3.5 (3.1 to 10.7) < 0.001 4.5 (5.03 to 12.9) < 0.001 3.5 (3.1 to 10.7) < 0.001 Note. SNP: single nucleotide polymorphism; BMI: body mass index. Table 5. Association of ADRA2A SNPs with ADP Inhibition by Multivariate Linear Regression Analysis
Additional analysis stratified by sex showed that in male patients, ADP inhibition was significantly different among the genotypes carrying rs11195419 (P = 0.003) and rs3750625 (P = 0.002) in additive model, and the homozygous groups had the lowest ADP inhibition. However, this difference was not found in female patients (Figure 2). Multivariate analysis also showed that rs11195419 and rs3750625 were predictors of ADP inhibition (95% CI: -28.6 to -4.2; P = 0.008 and 95% CI: -30.4 to -5.5; P = 0.005, respectively) in male patients, which was not observed in female patients (Table 6).
Characteristics Univariate Analysis Multivariate Analysis Coef (95% CI) P Coef (95% CI) P Male RS11195419 -2.9 (-31.3 to -6.3) 0.003 -2.6 (-28.6 to -4.2) 0.008 RS3750625 -3.2 (-33.3 to -7.8) 0.002 -2.8 (-30.4 to -5.5) 0.005 Female RS11195419 0.9 (-17.9 to 19.7) 0.928 0.1 (-17.5 to 20.2) 0.890 RS3750625 -0.2 (-19.2 to 16.3) 0.872 -0.1 (-19.2 to 16.6) 0.889 Table 6. Association of ADRA2A SNPs and ADP Inhibition by Univariate and Multivariate Linear Regression Analysis Stratificated by Sex
Genotype Distribution and Patient Characteristics
Association with ADP Inhibition and ADRA2A Genotypes
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No conflict of interest to declare.
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Variables RS553668 RS13306146 WT
(N = 334)HE
(N = 492)HO
(N = 198)P WT
(N = 587)HE
(N = 354)HO
(N = 83)P Age, years 59.1 ± 10.0 58.1 ± 10.4 58.6 ± 11.7 0.343 58.5 ± 10.2 58.6 ± 10.8 58.3 ± 12.3 0.974 Male, n (%) 242 (72.5) 385 (78.3) 146 (73.7) 0.134 438 (74.6) 269 (76.0) 66 (79.5) 0.601 BMI, kg/m2 26.1 ± 3.2 26.1 ± 3.2 25.9 ± 3.3 0.703 26.2 ± 3.2 25.9 ± 3.3 26.0 ± 3.6 0.325 Platelet, ×109/L 203.0 ± 52.2 202.5 ± 53.8 214.8 ± 59.2 0.019 202.8 ± 52.9 205.9 ± 54.9 217.3 ± 62.7 0.071 ACS, n (%) 98 (29.3) 159 (32.3) 69 (34.8) 0.399 175 (29.8) 116 (32.8) 35 (42.2) 0.070 DM, n (%) 116 (34.7) 141 (28.7) 51 (25.8) 0.059 189 (32.2) 99 (28.0) 20 (24.1) 0.181 Hypertension, n (%) 218 (65.3) 288 (58.5) 127 (64.1) 0.112 362 (61.7) 222 (62.7) 49 (59.0) 0.820 HCL, n (%) 285 (85.3) 414 (84.1) 166 (83.8) 0.866 494 (84.2) 299 (84.5) 72 (86.7) 0.830 Current smoking, n (%) 118 (35.3) 202 (41.1) 63 (31.8) 0.048 218 (37.1) 135 (38.1) 30 (36.1) 0.925 CHD family history, n (%) 4 (1.2) 4 (0.8) 4 (2.0) 0.411 9 (1.5) 2 (0.6) 1 (1.2) 0.409 Previous MI, n (%) 50 (15.0) 98 (19.9) 26 (13.1) 0.049 102 (17.4) 61 (17.2) 11 (13.3) 0.638 Previous PCI, n (%) 44 (13.2) 76 (15.4) 27 (13.6) 0.625 85 (14.5) 50 (14.1) 12 (14.5) 0.988 Previous CABG, n (%) 1 (0.3) 4 (0.8) 0 (0) 0.319 3 (0.5) 2 (0.6) 0 (0) 0.796 LAD, n (%) 199 (59.6) 273 (55.5) 119 (60.1) 0.379 349 (59.5) 190 (53.7) 52 (62.7) 0.140 LCX, n (%) 95 (28.4) 140 (28.5) 59 (29.8) 0.932 170 (29.0) 103 (29.1) 21 (25.3) 0.773 RCA, n (%) 151 (45.2) 227 (46.1) 88 (44.4) 0.913 263 (44.8) 168 (47.5) 35 (42.2) 0.597 LM, n (%) 17 (5.1) 22 (4.5) 11 (5.6) 0.818 29 (4.9) 18 (5.1) 3 (3.6) 0.851 Statin, n (%) 328 (98.2) 473 (96.1) 193 (97.5) 0.210 567 (96.6) 345 (97.5) 82 (98.8) 0.466 β-blocker, n (%) 293 (87.7) 438 (89.0) 178 (89.9) 0.722 522 (88.9) 312 (88.1) 75 (90.4) 0.832 ACEI/ARB, n (%) 205 (61.4) 285 (57.9) 114 (57.6) 0.554 341 (58.1) 214 (60.5) 49 (59.0) 0.776 PPIs, n (%) 66 (13.4) 58 (17.4) 38 (19.2) 0.109 94 (16.0) 55 (15.5) 13 (15.7) 0.980 DES, n (%) 331 (99.1) 488 (99.2) 197 (99.5) 0.878 584 (99.5) 350 (98.9) 82 (98.8) 0.522 BMS, n (%) 1 (0.3) 4 (0.8) 1 (0.5) 0.629 1 (0.2) 4 (1.1) 1 (1.2) 0.130 Ballooning only, n (%) 2 (0.6) 0 (0) 0 (0) 0.126 2 (0.3) 0 (0) 0 (0) 0.474 Note.*: P < 0.005; WT: Wild Type, HE: Heterozygote, HO: Homozygote, ADRA2A: the α2A-adrenergic receptor gene, BMI: body mass index, ACS: acute coronary syndrome, DM: diabetes mellitus, CHD: coronary heart disease, HCL: Hypercholesterolemia, MI: myocardial infarction, PCI: percutaneous coronary intervention, CABG: coronary artery bypass grafting, LAD:left anterior descendens, LCX: left circumflex, RCA: right coronary artery, ACEI: angiotensin conversion enzyme inhibitor, ARB: angiotensin receptor blocker, CCB: calcium channel blocker, PPI: proton pump inhibitor, DES: Drug-eluting stent, BMS: Bare mental stent. Table Appendix. Baseline characteristics by ADRA2A genotypes (rs553668 and rs13306146)