Impact of pharmacogenetics on aspirin resistance: a systematic review

Pharmacogenetics promises better control of diseases such as cardiovascular disease (CVD). Acetylsalicylic acid, aspirin, prevents the formation of an activating agent of platelet aggregation and vasoconstriction, and it is used to prevent CVD. Nevertheless, patients may have treatment failure due to genetic variants that modify the metabolism of the drug causing aspirin resistance (AR).

Objectives

To realize a systematic literature review to determine the impact of genetic variants on AR.

Methods

Articles published in the MEDLINE/PubMed, Cochrane, Scopus, LILACS, and SCIELO databases were systematically screened. A total of 290 articles were identified and 269 articles were excluded because they did not comply with the previously established inclusion criteria. A total of 20 case-control studies and 1 cohort was included.

Results

The genetic variants rs1126643 (ITGA2), rs3842787 (PTGS1), rs20417 (PTGS2), and rs5918 (ITGB3) were the most studied. As for relevance, of the 64 genetic variants evaluated by the articles, 14 had statistical significance (p< 0.05; 95% confidence interval [CI]) in at least one article. Among them, the following have had unanimous results: rs1371097 (P2RY1), rs1045642 (MDR1), rs1051931 and rs7756935 (PLA2G7), rs2071746 (HO1), rs1131882 and rs4523 (TBXA2R), rs434473 (ALOX12), rs9315042 (ALOX5AP), and rs662 (PON1), while these differ in real interference in AR: rs5918 (ITGB3), rs2243093 (GP1BA), rs1330344 (PTGS1), and rs20417 (PTGS2). As study limitations, we highlight the nonuniform methodologies of the analyzed articles and population differences.

Conclusion

It is noteworthy that pharmacogenetics is an expanding area. Therefore, further studies are needed to better understand the association between genetic variants and AR.

Keywords
Pharmacogenetics; Aspirin; Genetic Variation

Author (year)	Type of article	Country	Clinical condition	Sample number*	Aspirin resistant	Aspirin sensitive	Gene	Protective allele	Risk allele	Genetic variation	p-value	OR	CI	Resistance assessment method	Aspirin dose/day
Patel S. et al (2019)²³23 Patel S, Arya V, Saraf A, Bhargava M, Agrawal CS. Aspirin and Clopidogrel Resistance in Indian Patients with Ischemic Stroke and its Associations with Gene Polymorphisms: A Pilot Study. Ann Indian Acad Neurol 2019;22(02):147-152	Case-control	India	Ischemic stroke	65	2	62	CYP2C19	G	A	rs4244285 (CYP2C19*2)	0.171	NI	NI	Platelet Aggregation Measurement - LTA	75mg
	Case-control	India	Ischemic stroke	65	2	62	ITGA2B/ITGB3	T	C	rs5918 (PLA1/A2)	0.960	NI	NI	Platelet Aggregation Measurement - LTA	75mg
Yeo et al. (2018)³⁵35 Yeo KK, Armstrong EJ, López JE, et al. Aspirin and clopidogrel high ontreatment platelet reactivity and genetic predictors in peripheral arterial disease. Catheter Cardiovasc Interv 2018;91(07):1308-1317	Cohort	USA	Peripheral artery disease	154	31	123	PTGS1	A	G	rs10306114 (A842G)	NI	NI	NI	Platelet Aggregation Measurement - VerifyNow Assay	300mg
							PTGS1	C	T	rs3842787 (C22T)	NI	NI	NI
							PTGS1	C	A	rs5788 (C644A)	NI	NI	NI
							PTGS1	C	A	rs5789 (C714A)	NI	NI	NI
							ITGA2	C	T	rs1126643 (C807T)	NI	NI	NI
							ITGA2	G	A	rs1062535 (873G/A)	NI	NI	NI
							ITGA2	C	T	rs1126643 (C807T)	NI	NI	NI
							ITGB3	T	C	rs5918 (PLA1/A2)	NI	NI	NI
							GP6	C	T	rs1613662 (C13254T)	NI	NI	NI
							P2RY12	C	T	rs1065776 (893C > T)	NI	NI	NI
							F13A1	G	T	rs5985 (V34L)	NI	NI	NI
							PON1	A	G	rs662 (A576G)	0.005	NI	NI
Wang et al. (2017)²⁸28 Wang H, Sun X, Dong W, et al. Association of GPIa and COX-2 gene polymorphism with aspirin resistance. J Clin Lab Anal 2018;32 (04):e22331	Case-control	China	Ischemic stroke	97	43	54	ITGA2	C	T	rs1126643 (C807T)	0.210	NI	NI	Platelet Aggregation Measurement - PL-11 platelet analyzer	100mg
	Case-control	China	Ischemic stroke	97	43	54	PTGS2	G	C	rs20417 (G765C)	0.69	NI	NI	Platelet Aggregation Measurement - PL-11 platelet analyzer	100mg
Strisciuglio et al. (2017)³⁶36 Strisciuglio T, Barbato E, De Biase C, et al. T2238C Atrial Natriuretic Peptide Gene Variant and the Response to Antiplatelet Therapy in Stable Ischemic Heart Disease Patients. J Cardiovasc Transl Res 2018;11(01):36-41	Case-control	Belgium	Stable CAD patients undergoing elective PCI	597	NI	NI	NPPA	T	C	rs5065 (T2238C)	0.7	NI	NI	Platelet Aggregation Measurement - VerifyNow P2Y12	500mg
Yi et al. (2017)¹⁹19 Yi X, Wang C, Zhou Q, Lin J. Interaction among COX-2, P2Y1 and GPIIIa gene variants is associated with aspirin resistance and early neurological deterioration in Chinese stroke patients. BMC Neurol 2017;17(01):4	Case-control	China	Ischemic stroke	850	175	630	PTGS1	C	T	rs1236913	0.99**	NI	NI	Platelet Aggregation Measurement - LTA	200mg (14 days) and follow-up with 100mg
							PTGS1	C	T	rs3842787	0.76**	NI	NI
							PTGS2	A	G	rs689466	0.89**	NI	NI
							PTGS2	G	C	rs20417	0.26**	NI	NI
							TXAS1	G	A	rs194149	0.42**	NI	NI
							TXAS1	T	C	rs2267679	0.53**	NI	NI
							TXAS1	G	T	rs41708	0.72**	NI	NI
							P2RY1	A	G	rs701265	0.48**	NI	NI
							P2RY1	A	G	rs1439010	0.32**	NI	NI
							P2RY1	C	T	rs1371097	0.01**	NI	NI
							P2RY12	C	T	rs16863323	0.21**	NI	NI
							P2RY12	G	A	rs9859538	0.16**	NI	NI
							ITGB3	A	G	rs2317676	0.24**	NI	NI
							ITGB3	A	G	rs11871251	0.51**	NI	NI
Peng et al. (2016)²⁰20 Peng LL, Zhao YQ, Zhou ZY, et al. Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. Acta Pharmacol Sin 2016;37(11):1442-1448	Case-control	China	Ischemic stroke	283	250	33	ABCB1	C	T	rs1045642	0.021	0.421	0.233-0.759	Platelet Aggregation Measurement - TXB2 ELISA kit	100mg
							TBXA2R	G	A	rs1131882	0.028	2.712	1.080-6.810
							PLA2G7	A	G	rs1051931	0.023	8.233	1.590-42.638
							PLA2G7	C	A	rs7756935	0.023	8.233	1.590-42.638
							PEAR1	G	T	rs12566888	0.378	0.660	0.260-1.671
							PEAR1	G	A	rs12566888	0.378	0.660	0.260-1.671
Yi et al. (2016)⁸8 Yi X, Cheng W, Lin J, Zhou Q, Wang C. Interaction between COX-1 and COX-2 Variants Associated with Aspirin Resistance in Chinese Stroke Patients. J Stroke Cerebrovasc Dis 2016;25(09): 2136-2144	Case-control	China	Ischemic stroke	850	175	630	PTGS1	T	C	rs1236913	0.95**	NI	NI	Platelet Aggregation Measurement- LTA	200mg (14 days) and follow-up with 100mg
							PTGS1	C	T	rs3842787	0.78**	NI	NI
							PTGS2	T	C	rs689466	0.82**	NI	NI
							PTGS2	G	C	rs20417	0.42**	NI	NI
Derle et al. (2016)³3 Derle E, Öcal R, Kibaroğlu S, et al. Aspirin resistance in cerebro-vascular disease and the role of glycoprotein IIIa polymorphism in Turkish stroke patients. Blood Coagul Fibrinolysis 2016;27(02): 169-175	Case-control	Turkey	Acute vascular event	208	67	141	ITGB3	T	C	rs5918 (PLA1/A2)	0.277	NI	NI	Platelet Aggregation Measurement - PFA-100 system	100-300mg
Wang et al. (2014)²⁴24 Wang BY, Tan SJ. Platelet glycoprotein IIIa gene polymorphism (Leu33Pro) and aspirin resistance in a very elderly Chinese population. Genet Test Mol Biomarkers 2014;18(06): 389-393	Case-control	China	> 80 years old	450	236	214	ITGB3	T	C	rs5918 (PLA1/A2)	0.002	NI	NI	Platelet Aggregation Measurement - LTA	100mg
Al-Azzam et al. (2013)²⁷27 Al-Azzam SI, Alzoubi KH, Khabour OF, Tawalbeh D, Al-Azzeh O. The contribution of platelet glycoproteins (GPIa C807T and GPIba C-5T) and cyclooxygenase 2 (COX-2G-765C) polymorphisms to platelet response in patients treated with aspirin. Gene 2013;526 (02):118-121	Case-control	Jordan	Adults	584	92	492	ITGA2	C	T	rs1126643 (C807T)	0.116	NI	NI	Platelet Aggregation Measurement - Multiplate Analyzer system	100mg
							GP1BA	T	C	rs2243093	0.003	NI	NI
							PTGS2	G	C	rs20417	0.485	NI	NI
Li et al. (2012)²⁹29 Li XL, Cao J, Fan L, et al. Genetic polymorphisms of HO-1 and COX- 1 are associated with aspirin resistance defined by light transmittance aggregation in Chinese Han patients. Clin Appl Thromb Hemost 2013;19(05):513-521	Case-control	China	CAD, stroke, and peripheral artery disease	431	36	231	PTGS1	C	T	rs1888943	0.92	NI	NI	Platelet Aggregation Measurement - LTA	75-160mg
							PTGS1	A	G	rs1330344	0.1	NI	NI
							PTGS1	C	T	rs3842787	0.92	NI	NI
							PTGS1	G	A	rs5787	0.92	NI	NI
							PTGS1	C	A	rs5789	1	NI	NI
							PTGS1	G	A	rs5794	1	NI	NI
							PTGS2	G	C	rs20417	1	NI	NI
							PTGS2	C	G	rs5277	0.24	NI	NI
							HO1	A	T	rs2071746	0.04	NI	NI
Wang et al. (2013)²¹21 Wang Z, Gao F, Men J, Yang J, Modi P, Wei M. Polymorphisms and high on-aspirin platelet reactivity after off-pump coronary artery bypass grafting. Scand Cardiovasc J 2013;47(04):194-199	Case-control	China	Patientsunderwent primary OPCAB	210	62	148	TBXA2R	T	C	rs4523 (T924C)	0.001	4.479	1.811-11.077	Platelet Aggregation Measurement - LTA	100mg
							ITGB3	T	C	rs5918 (PLA1/A2)	NI	NI	NI
							P2RY1	A	G	rs701265 (A1622G)	0.724	1.178	0.473-2.934
							GP1BA	C	T	rs6065 (C1018T)	NI	NI	NI
Sharma et al. (2013)³²32 Sharma V, Kaul S, Al-Hazzani A, Alshatwi AA, Jyothy A, Munshi A. Association of COX-2 rs20417 with aspirin resistance. J Thromb Thrombolysis 2013;35(01):95-99	Case-control	India	Ischemic stroke	450	217	233	PTGS2	G	C	rs20417 (-765G/C)	CC: p= 0.016 GC:p= 0.02	CC:OR-3.157 GC: OR-1.745	CC: 1.241-8.033GC: 1.059-2.875	Clinical outcome	75-325mg
Sharma et al. (2013)¹⁷17 Sharma V, Dadheech S, Kaul S, Jyothy A, Munshi A. Association of ALOX5AP1 SG13S114T/A variant with ischemic stroke, stroke subtypes and aspirin resistance. J Neurol Sci 2013;331(1-2):108-113	Case-control	India	Ischemic stroke	610	307	303	ALOX5AP	T	A	rs9315042 (SG13S114T/A)	<0.001	2.983	1.884-4.723	Clinical outcome	75-325mg
Fan et al. (2012)	Case-control	China	CAD, hypertension, peripheral artery disease and stroke	431	38	393	PTGS1	A	G	rs1330344	0.01	1.82	1.13-2.92	Platelet Aggregation Measurement - LTA and TEG Platelet Mapping Assay	75-100 mg
							PTGS1	C	T	rs1888943	0.59	NI	NI
							PTGS1	C	T	rs3842787	0.66	NI	NI
							PTGS1	G	A	rs5787	0.49	NI	NI
							PTGS1	C	A	rs5789	1	NI	NI
							PTGS1	G	A	rs5794	1	NI	NI
Sharma et al. (2012)³³33 Sharma V, Kaul S, Al-Hazzani A, et al. Association of C3435T multi drug resistance gene-1 polymorphism with aspirin resistance in ischemic stroke and its subtypes. J Neurol Sci 2012;315(1-2):72-76	Case-control	India	Ischemic stroke	560	338	222	ABCB1	C	T	rs1045642	0.012	1.85	1.142-3.017	Clinical outcome	75-325 mg/dia
Gao et al. (2011)²²22 Gao F, Wang ZX, Men JL, Ren J, Wei MX. Effect of polymorphism and type II diabetes on aspirin resistance in patients with unstable coronary artery disease. Chin Med J (Engl) 2011;124(11): 1731-1734	Case-control	China	Patients underwent primary OPCAB	262	23	239	GP1BA	C	T	rs6065 (C1018T)	1	NI	NI	Platelet Aggregation Measurement - LTA	100mg
							ITGB3	T	C	rs5918 (P1A1/A2)	1	NI	NI
							P2RY1	A	G	rs701265 (A1622G)	0.991	NI	NI
							TBXA2R	T	C	rs4523 (T924C)	0.01	NI	NI
Chakroun et al. (2011)³¹31 Chakroun T, Addad F, Yacoub S, et al. The cyclooxygenase-1 C50T polymorphism is not associated with aspirin responsiveness status in stable coronary artery disease in Tunisian patients. Genet Test Mol Biomarkers 2011;15(7-8):513-516	Case-control	Tunisia	Stable CAD	125	NI	NI	PTGS1	C	T	rs3842787 (C50T)	Urinary TxB2: 0.1PFA-100: 0.43	NI	NI	Platelet Aggregation Measurement - PFA-100 system and Urinary 11-dehydro-TXB2	250mg
Voora et al. (2011)²⁶26 Voora D, Horton J, Shah SH, Shaw LK, Newby LK. Polymorphisms associated with in vitro aspirin resistance are not associated with clinical outcomes in patients with coronary artery disease who report regular aspirin use. Am Heart J 2011;162(01):166-72.e1	Case-control	USA	Coronary stenosis ≥ 75%	3449	865	2584	GNB3	C	T	rs5443 (C825T)	> 0.05	Black: 1.15 White: 0.93	Black: 0.71-1.87 White: 0.82-1.07	Clinical Outcome	Two groups: < 81mg and > 81mg
							ITGA2	C	T	rs1126643 (C807T)		Black: 1.10 White: 0.99	Black: 0.82-1.46 White: 0.87-1.14
							ITGB3	T	C	rs5918		Black: 1.03 White: 0.98	Black: 0.71-1.50 White: 0.85-1.13
							GP6	A	G	rs1613662		Black: 0.89 White: 0.99	Black: 0.66-1.20 White: 0.86-1.15
							GP1BA	T	C	rs2243093		Black: 0.84 White: 1.01	Black: 0.62-1.14 White: 0.86-1.18
							PEAR1	A	C	rs2768759		Black: 1.05 White: 0.95	Black: 0.46-2.41 White: 0.83-1.09
							VAV3	A	C	rs6583047		Black: 1.06 White: 1.02	Black: 0.80-1.42 White: 0.89-1.16
							F2R	A	T	rs168753		Black: 0.96 White: 1.06	Black: 0.60-1.54 White: 0.91-1.23
							THBS1	A	G	rs2228262		Black: 0.68 White: 1.03	Black: 0.34-1.36 White: 0.88-1.21
							PTGS1	C	T	rs3842787		Black: 1.29 White: 1.06	Black: 0.94-1.77 White: 0.88-1.29
							ADRA2A	G	C	rs1800544		Black: 0.98 White: 0.97	Black: 0.63-1.51 White: 0.85-1.10
Pamukcu et al. (2010)²⁵25 Pamukcu B, Oflaz H, Onur I, Hancer V, Yavuz S, Nisanci Y. Impact of genetic polymorphisms on platelet function and aspirin resistance. Blood Coagul Fibrinolysis 2010;21(01):53-56	Case-control	Turkey	Stable CAD	126	30	96	F5	G	A	rs6025 (G1691A)	0.302	NI	NI	Platelet Aggregation Measurement - PFA-100 system	NI (The p-value for the difference between the resistant and sensitive groups was 0.681)
							F5	A	G	rs1800595 (A4070G - H1299R)	0.191
							F2	G	A	rs1799963 (G20210A)	0.644
							F13A1	G	T	rs5985 (V34L)	0.480
							FGB	G	A	rs1800790 (G455A)	0.814
							SERPINE1	A	G	rs1799889 (4G/5G)	0.656
							ITGB3	T	C	rs5918 (HPA1a/b)	0.623
							MTHFR	C	T	rs1801133 (C677T)	0.362
							MTHFR	A	C	rs1801131 (A1298C)	0.421
							ACE	Ins	Del	rs1799752 (ACE I/D)	0.713
							APOB	G	A	rs5742904 (R3500Q)	1
							APOE	T	C	rs429358 (C112R)	0.695
							APOE	T	C	rs429358 (C158A)	0.695
Carroll et al. (2010)³⁴34 Carroll RC, Worthington RE, Craft RM, et al. Post interventional cardiology urinary thromboxane correlates with PlateletMapping detected aspirin resistance. Thromb Res 2010;125(04): e118-e122	Case-control	USA	Candidates for interventional cardiology on aspirin therapy	81	27	54	ALOX12	A	G	rs434473	0.043	NI	NI	Platelet Aggregation Measurement - TEG Platelet mapping	Not uniform
							ALOX15B	G	A	rs4792147	0.440
							ALOX12	G	A	rs1126667	0.580
							ALOX15	G	A	rs3892408	NI

Biomarker (Pharmacogene)	Alleles	Refs.
PON1	rs662	³⁵35 Yeo KK, Armstrong EJ, López JE, et al. Aspirin and clopidogrel high ontreatment platelet reactivity and genetic predictors in peripheral arterial disease. Catheter Cardiovasc Interv 2018;91(07):1308-1317
P2RY1	rs1371097	¹⁹19 Yi X, Wang C, Zhou Q, Lin J. Interaction among COX-2, P2Y1 and GPIIIa gene variants is associated with aspirin resistance and early neurological deterioration in Chinese stroke patients. BMC Neurol 2017;17(01):4
ABCB1	rs1045642	²⁰20 Peng LL, Zhao YQ, Zhou ZY, et al. Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. Acta Pharmacol Sin 2016;37(11):1442-1448,³³33 Sharma V, Kaul S, Al-Hazzani A, et al. Association of C3435T multi drug resistance gene-1 polymorphism with aspirin resistance in ischemic stroke and its subtypes. J Neurol Sci 2012;315(1-2):72-76
TBXA2R	rs1131882, rs 4523	²⁰20 Peng LL, Zhao YQ, Zhou ZY, et al. Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. Acta Pharmacol Sin 2016;37(11):1442-1448,²¹21 Wang Z, Gao F, Men J, Yang J, Modi P, Wei M. Polymorphisms and high on-aspirin platelet reactivity after off-pump coronary artery bypass grafting. Scand Cardiovasc J 2013;47(04):194-199
PLA2G7	rs1051931, rs7756935	²⁰20 Peng LL, Zhao YQ, Zhou ZY, et al. Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy. Acta Pharmacol Sin 2016;37(11):1442-1448
ITGB3	rs5918	²⁴24 Wang BY, Tan SJ. Platelet glycoprotein IIIa gene polymorphism (Leu33Pro) and aspirin resistance in a very elderly Chinese population. Genet Test Mol Biomarkers 2014;18(06): 389-393
GP1BA	rs2243093	²⁷27 Al-Azzam SI, Alzoubi KH, Khabour OF, Tawalbeh D, Al-Azzeh O. The contribution of platelet glycoproteins (GPIa C807T and GPIba C-5T) and cyclooxygenase 2 (COX-2G-765C) polymorphisms to platelet response in patients treated with aspirin. Gene 2013;526 (02):118-121
HO1	rs2071746	²⁹29 Li XL, Cao J, Fan L, et al. Genetic polymorphisms of HO-1 and COX- 1 are associated with aspirin resistance defined by light transmittance aggregation in Chinese Han patients. Clin Appl Thromb Hemost 2013;19(05):513-521
PTGS2	rs20417	¹⁷17 Sharma V, Dadheech S, Kaul S, Jyothy A, Munshi A. Association of ALOX5AP1 SG13S114T/A variant with ischemic stroke, stroke subtypes and aspirin resistance. J Neurol Sci 2013;331(1-2):108-113
ALOX5AP	rs9315042	¹⁷17 Sharma V, Dadheech S, Kaul S, Jyothy A, Munshi A. Association of ALOX5AP1 SG13S114T/A variant with ischemic stroke, stroke subtypes and aspirin resistance. J Neurol Sci 2013;331(1-2):108-113
PTGS1	rs1330344	²⁹29 Li XL, Cao J, Fan L, et al. Genetic polymorphisms of HO-1 and COX- 1 are associated with aspirin resistance defined by light transmittance aggregation in Chinese Han patients. Clin Appl Thromb Hemost 2013;19(05):513-521,³⁰30 Fan L, Cao J, Liu L, et al. Frequency, risk factors, prognosis, and genetic polymorphism of the cyclooxygenase-1 gene for aspirin resistance in elderly Chinese patients with cardiovascular disease. Gerontology 2013;59(02):122-131
ALOX12	rs434473	³⁴34 Carroll RC, Worthington RE, Craft RM, et al. Post interventional cardiology urinary thromboxane correlates with PlateletMapping detected aspirin resistance. Thromb Res 2010;125(04): e118-e122

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[1] Address for correspondence Leslie Ecker Ferreira (email: leslie.ferreira@univille.br).