Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent
Abstract
1. Introduction
2. Results
2.1. Patient Characteristics
2.2. Two-Stage Association Study
- ○
- “Intervention vs. non-intervention” (see Supplementary Data, Supplementary Results, p. 7)
- ○
- “Event vs. non-event” (see Supplementary Data, Supplementary Results, p. 9 or in more detail in the publication by Antúnez-Rodríguez et al. [2])
- ○
- “Case vs. control” (see Supplementary Data, Supplementary Results, p. 11)
2.2.1. Secondary CV Events After Clopidogrel Treatment
2.2.2. Secondary CV Events After Prasugrel Treatment
2.3. Random Forest Models
2.3.1. Secondary CV Events Regardless of Prescribed Therapy
2.3.2. Secondary CV Events Following Clopidogrel Treatment
2.3.3. Secondary CV Events Following Prasugrel Treatment
3. Discussion
4. Methods
4.1. Study Population
- ○
- G1 group: a cohort of ACS-PCI-stent patients on antiplatelet therapy (guided or not by genetic testing) who experienced MACEs and/or bleeding during one-year follow-up (n = 109). This group was divided into two subgroups:
- “intervention group” (G1.1), in which carriers of CYP2C19 LoF alleles (*2 or *3) and/or the TT risk genotype for ABCB1 C3435T received prasugrel or ticagrelor, while patients with normal CYP2C19 and ABCB1 gene function received clopidogrel (n = 50).
- “non-intervention group” (G1.2), in which all patients were primarily treated with clopidogrel, regardless of their genetic profile (n = 59).
- ○
- G2 group: a cohort of ACS-PCI-stent patients on PGx-guided antiplatelet therapy who did not experience MACEs and/or bleeding (n = 135).
- ○
- G3 group: a cohort of patients without structural CV disease (n = 99).
4.2. Genetic Analysis
4.3. Statistical Analysis
4.3.1. Association Study
- ○
- “intervention” vs. “non-intervention” (G1.1 vs. G1.2);
- ○
- “event” vs. “non-event” (G1 vs. G2);
- ○
- “case” vs. “control” (G1&G2 vs. G3).
4.3.2. Random Forest Analysis
- ○
- Event vs. non-event” comparison, regardless of the antiplatelet drug received;
- ○
- “Event vs. non-event” comparison in patients taking clopidogrel;
- ○
- “Event vs. non-event” comparison in patients taking prasugrel.
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACS | acute coronary syndrome |
BMI | body mass index |
CAD | coronary artery disease |
CV | cardiovascular |
CYP | cytochrome P450 |
DAPT | dual antiplatelet therapy |
GTEx | Genotype-Tissue Expression Project |
HDL | high-density lipoprotein |
HTPR | high on-treatment platelet reactivity |
LD | linkage disequilibrium |
LDL | low-density lipoprotein |
LoF | loss-of-function |
MACE | major adverse cardiovascular event |
MAF | minor allele frequency |
PCI | percutaneous coronary intervention |
PGx | pharmacogenomics |
RCT | reverse cholesterol transport |
SNP | single nucleotide polymorphisms |
UGT | uridine diphosphate (UDP)-glucuronosyltransferase |
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ACS Patients | Controls | |||||
---|---|---|---|---|---|---|
All (N = 343) | G1 (N = 109) | G2 (N = 135) | p-Value * | G3 (N = 99) | p-Value ** | |
Age | 65.9 (11.1) | 66.8 (11.4) | 64.8 (12.3) | 0.202 | 66.4 (8.8) | 0.339 |
Gender | ||||||
Male | 232 (67.6) | 78 (71.6) | 101 (74.8) | 0.670 | 53 (53.5) | 0.002 |
Female | 111 (32.4) | 31(28.4) | 34 (25.2) | 46 (46.5) | ||
BMI | 28.6 (4.6) | 28.9 (4.6) | 28.4 (4.5) | 0.369 | NA | NA |
Ethnic origin | ||||||
Caucasian | 335 (97.7) | 105 (96.3) | 132 (97.8) | 0.517 | 98 (99.0) | 0.423 |
Gypsy | 6 (1.7) | 3 (2.8) | 3 (2.2) | 0 (0.0) | ||
Moroccan | 2 (0.6) | 1 (0.9) | 0 (0.0) | 1 (1.0) | ||
Cv history | 93 (27.1) | 52 (47.7) | 41 (30.4) | 0.008 | 0 | <0.001 |
All (N = 244) | G1 (N = 109) | G2 (N = 135) | p-Value | |
---|---|---|---|---|
Acetylsalicylic acid | 244 (100) | 109 (100) | 135 (100) | 1.000 |
Antiplatelet therapy | ||||
Clopidogrel | 169 (69.3) | 82 (75.2) | 87 (64.4) | 0.035 |
Prasugrel | 73 (29.9) | 25 (22.9) | 48 (35.6) | |
Ticagrelor | 2 (0.8) | 2 (1.8) | 0 (0.0) | |
DAPT duration | ||||
1 month | 14 (5.7) | 11 (10.1) | 3 (2.2) | 0.006 |
3 months | 2 (0.8) | 2 (1.8) | 0 (0.0) | |
6 months | 2 (0.8) | 2 (1.8) | 0 (0.0) | |
12 months or more | 226 (92.6) | 94 (86.2) | 132 (97.8) |
Comparison | SNP | Alleles | Gene | Functional Consequence | Biological Process Involved |
---|---|---|---|---|---|
Intervention vs. non-intervention | rs72934556 | T>G | NBEAL1 | synonymous | Lipid metabolism |
rs2289843 | A>T | KALRN | splice region | Endothelial dysfunction, atherosclerosis | |
Event vs. non-event | rs2472434 | A>C | ABCA1 | intronic | Lipid metabolism, inflammation |
rs17618244 | G>A | KLB | missense | Lipid metabolism | |
rs3827066 | C>T | ZNF335 | intronic | Lipid metabolism | |
Case vs. control | rs11076799 | G>A | ADCY9 | intronic | Endothelial dysfunction |
rs5370 | G>T | EDN1 | missense | Endothelial dysfunction, inflammation, lipid metabolism | |
rs1800566 | G>A | NQO1 | missense | Inflammation, atherogenesis |
SNP | Chr | Position | Ref | Alt | Gene | Gene Role | Func. | MAF | p-Value | Beta | SD |
---|---|---|---|---|---|---|---|---|---|---|---|
rs4244285 | 10 | 96541616 | G | A | CYP2C19 | drug metabolism | synon. | 0.15 | 0.00046 | −1.9297 | 0.5785 |
rs4986894 | 10 | 96522365 | T | C | CYP2C19 | drug metabolism | upstream | 0.15 | 0.00046 | −1.9297 | 0.5785 |
rs34828128 | 3 | 56667213 | T | C | FAM208A | unknown | synon. | 0.02 | 0.00085 | −2.2830 | 0.7476 |
rs2472434 | 9 | 107623249 | A | C | ABCA1 | disease predisposition | intronic | 0.28 | 0.00171 | −0.8835 | 0.2836 |
rs17618244 | 4 | 39448529 | G | A | KLB | disease predisposition | missense | 0.19 | 0.00194 | 0.8797 | 0.2859 |
rs4986938 | 14 | 64699816 | C | T | ESR2 | disease predisposition | UTR3 | 0.38 | 0.00251 | −0.6907 | 0.2300 |
SNP | Chr | Position | Ref | Alt | Gene | Func. | MAF | p-Value | Beta | SD |
---|---|---|---|---|---|---|---|---|---|---|
rs2235048 | 7 | 87138511 | G | A | ABCB1 | intronic | 0.47 | 0.03322 | 0.6291 | 0.2961 |
rs28365062 | 4 | 69964271 | A | G | UGT2B7 | synon. | 0.14 | 0.00917 | 0.8886 | 0.3429 |
rs7439366 | 4 | 69964338 | T | C | UGT2B7 | missense | 0.48 | 0.03090 | 0.5158 | 0.2394 |
rs4244285 | 10 | 96541616 | G | A | CYP2C19 | synon. | 0.15 | 0.00046 | −1.9297 | 0.5785 |
rs4986894 | 10 | 96522365 | T | C | upstream | |||||
rs11509438 | 10 | 106027059 | G | A | GSTO1 | missense | 0.03 | 0.02745 | −1.4006 | 0.6430 |
rs1907637 | 3 | 151104838 | A | G | P2RY12 | upstream | 0.87 | 0.01814 | 0.9126 | 0.3876 |
rs6809699 | 3 | 151056598 | A | C | P2RY12 | synon. | 0.83 | 0.03925 | 0.6609 | 0.3215 |
rs2046934 | 3 | 151057642 | G | A | intronic | |||||
rs10935838 | 3 | 151058247 | A | G | intronic |
SNP | Chr | Position | Ref | Alt | Gene | Gene Role | Func. | MAF | p-Value | Beta | SD |
---|---|---|---|---|---|---|---|---|---|---|---|
rs150276286 | 16 | 81902879 | C | G | PLCG2 | disease predisposition | synon. | 0.01 | 0.00026 | −3.6496 | 1.0675 |
rs13047599 | 21 | 34926260 | C | T | SON | unknown | missense | 0.67 | 0.00057 | −1.3065 | 0.3844 |
rs2742343 | 2 | 179569436 | A | G | TTN | disease predisposition | synon. | 0.03 | 0.00062 | −3.1466 | 1.0184 |
rs3732511 | 3 | 56766435 | C | G | ARHGEF3 | disease predisposition | synon. | 0.12 | 0.00062 | −1.8055 | 0.5398 |
rs2888805 | 12 | 104380734 | G | A | TDG | unknown | missense | 0.10 | 0.00079 | −2.5707 | 0.8042 |
rs6686 | 10 | 12209752 | T | C | NUDT5 | unknown | synon. | 0.50 | 0.00104 | −1.2772 | 0.3958 |
rs61781311 | 1 | 66087620 | G | T | LEPR | disease predisposition | intronic | 0.17 | 0.00105 | −1.3725 | 0.4255 |
rs2472434 | 9 | 107623249 | A | C | ABCA1 | disease predisposition | intronic | 0.28 | 0.00572 | −1.2671 | 0.4631 |
rs3827066 | 20 | 44586023 | C | T | ZNF335 | disease predisposition | intronic | 0.17 | 0.02880 | 1.0502 | 0.4836 |
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Antúnez-Rodríguez, A.; García-Rodríguez, S.; Pozo-Agundo, A.; Sánchez-Ramos, J.G.; Moreno-Escobar, E.; Triviño-Juárez, J.M.; Álvarez-Cubero, M.J.; Martínez-González, L.J.; Dávila-Fajardo, C.L. Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent. Int. J. Mol. Sci. 2025, 26, 9766. https://doi.org/10.3390/ijms26199766
Antúnez-Rodríguez A, García-Rodríguez S, Pozo-Agundo A, Sánchez-Ramos JG, Moreno-Escobar E, Triviño-Juárez JM, Álvarez-Cubero MJ, Martínez-González LJ, Dávila-Fajardo CL. Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent. International Journal of Molecular Sciences. 2025; 26(19):9766. https://doi.org/10.3390/ijms26199766
Chicago/Turabian StyleAntúnez-Rodríguez, Alba, Sonia García-Rodríguez, Ana Pozo-Agundo, Jesús Gabriel Sánchez-Ramos, Eduardo Moreno-Escobar, José Matías Triviño-Juárez, María Jesús Álvarez-Cubero, Luis Javier Martínez-González, and Cristina Lucía Dávila-Fajardo. 2025. "Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent" International Journal of Molecular Sciences 26, no. 19: 9766. https://doi.org/10.3390/ijms26199766
APA StyleAntúnez-Rodríguez, A., García-Rodríguez, S., Pozo-Agundo, A., Sánchez-Ramos, J. G., Moreno-Escobar, E., Triviño-Juárez, J. M., Álvarez-Cubero, M. J., Martínez-González, L. J., & Dávila-Fajardo, C. L. (2025). Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent. International Journal of Molecular Sciences, 26(19), 9766. https://doi.org/10.3390/ijms26199766