Correlation P2Y12 Genetic Polymorphism As Risk Factor of Clopidogrel Resistance in Indonesian Stroke Patients

Figures & data

Table 1 Demographic Characteristics and Clinical Data of Subjects

Characteristics of Subjects	n (%)	Mean (±SD) / Median (Min-Max)
Gender
Male	66 (58.9%)
Female	46 (41.1%)
Age (year)		57.1 (±10.6)/ 57.5 (25–80)
> 57	57 (50.9%)
≤57	55 (49.1%)
BMI (kg/m^2)		24.9 (±4.7)/24.3 (15.6–45.8)
> 25	48 (42.9%)
≤ 25	64 (57.1%)
DM history
Yes	37 (33.0%)
No	75 (67.0%)
Verify now		115.2 (±71.3)/105.5 (1–273)
No response (PRU: > 208)	16 (14.3%)
Response (PRU: 95–208)	51 (45.5%)
Risk of hemorrhage (PRU: < 95)	45 (40.2%)

Abbreviations: BMI, body mass index; DM, Diabetes Mellitus; SD, standard deviation; min, minimum; max, maximum; PRU, P2Y12 Reaction Unit.

Table 2 Examination of Gene P2Y12

	Wild Type Homozygote	Heterozygote	Mutant Homozygote
P2Y12 (C34T)	75 (67%)	31 (27.7%)	6 (5.4%)
P2Y12 (G52T)	74 (66.1%)	34 (30.4%)	4 (3.6%)

Table 3 Characteristics of Adjunctive Examination Results

Results of Examination	n (%)	Mean (±SD) / Median (Min-Max)
Hemoglobin (g/dL)		13.8 (±1.6)/13.9 (7.9–18.4)
≤ 13.9	57 (50.9%)
> 13.9	55 (49.1%)
HbA1c (%)		6.5 (±2.3)/5.7 (4.0–15.0)
≥ 6.5	37 (33.0%)
< 6.5	75 (67.0%)
FBG (mg/dL)		129.7 (±60.8)/109.5 (73–449)
≥ 126	38 (33.9%)
< 126	74 (66.1%)
Total Cholesterol (mg/dL)		191.8 (±50.9)/189.5 (93–379)
≥ 200	49 (43.8%)
< 200	63 (56.3%)
HDL (mg/dL)		52.2 (±14.9)/52.2 (22–102)
≥ 60	32 (28.6%)
< 60	80 (71.4%)
LDL (mg/dL)		127.0 (±40.6)/125 (38–269)
≥ 100	86 (76.8%)
< 100	26 (23.2%)
Triglycerides (mg/dL)		159.8 (±85.7)/140 (43–552)
≥ 150	47 (42.0%)
< 150	65 (58.0%)
AST (IU/L)		22.2 (±20.7)/19 (8–220)
≥34	8 (7.1%)
<34	104 (92.9%)
ALT (IU/L)		25.2 (±23.7)/20 (6–205)
≥55	5 (4.5%)
<55	107 (95.5%)
Hepatobiliary USG
Fatty liver	60 (53.6%)
None	52 (46.4%)

Abbreviations: BMI, body mass index; HbA1c, hemoglobin A1c; FBG, fasting blood glucose; HDL, high- density lipoprotein; AST, aspartate aminotransferase; ALT, alanine Aminotransferase; LDL, low-density lipoprotein; USG, ultrasonography; SD, standard deviation; min, minimum; max, maximum.

Table 4 Correlation Between Adjunctive Examination and P2Y12

Laboratory Result	P2Y12 G52T n (%)		p	OR (95% CI)	P2Y12 C34T n (%)		p	OR (95% CI)
	Homozygote	Non-Homozygote			Homozygote	Non-Homozygote
Hemoglobin (g/dL)
≤ 13.9	32 (56.1%)	25 (43.9%)	0.024*^†	0.396 (0.176–0.893)	37 (64.9%)	20 (35.1%)	0.638*	0.671 (0.291–1.547)
> 13.9	42 (76.4%)	13 (23.6%)			38 (69.1%)	17 (30.9%)
AST (IU/L)
≥34	6 (75.0%)	2 (25.0%)	0.580*	1.588 (0.305–8.274)	4 (50.0%)	4 (50.0%)	0.290*	0.614 (0.138–2.740)
<34	68 (65.4%)	36 (34.6%)			71 (68.3%)	33 (31.7%)
ALT (IU/L)
≥55	3 (60.0%)	2 (40.0%)	0.769*	0.761 (0.122–4.758)	3 (60.0%)	2 (40.0%)	0.735*	1.558 (0.167–14.516)
<55	71 (66.4%)	36 (33.6%)			72 (67.3%)	35 (32.7%)
USG
Fatty Liver	43 (71.7%)	17 (28.3%)	0.179*	1.713 (0.779–3.771)	35 (58.3%)	25 (41.7%)	0.037*^†	0.647 (0.278–1.505)
Non-Fatty Liver	31 (59.6%)	21 (40.4%)			40 (76.9%)	12 (23.1%)

Note: *Chi-square; ^†p < 0.05.

Abbreviations: AST, aspartate aminotransferase; ALT, alanine Aminotransferase; LDL, low-density lipoprotein; USG, ultrasonography; OR, Odd ratio; CI, confidence interval.

Table 5 Correlation Between P2Y12 and Clopidogrel Resistance

Genetic Variant	No Response n (%)	Response n (%)	P	OR (95% CI)
P2Y12 (G52T)			0.744	0.833 (0.278–2.497)
Homozygote	10 (13.5%)	64 (86.5%)
Non-homozygote	6 (15.8%)	32 (84.2%)
P2Y12 (C34T)			0.682	0.795 (0.265–2.385)
Homozygote	10 (13.3%)	65 (86.7%)
Non-homozygote	6 (16.2%)	31 (83.8%)

Abbreviations: OR, Odd ratio; CI, confidence interval.

Table 6 Comparison of the Mean BMI in the Response and Non-Response Groups

	BMI Response (kg/m2)	BMI No Response (kg/m2)
This study	25.1	24.1
Legrand et al^Citation31	27	28
Price et al^Citation32	29	31

Figure 1 Clopidogrel Metabolism.

Notes: Clopidogrel is a prodrug, 85% of clopidogrel is hydrolyzed by esterases and converted to inactive derivatives, another 15% is metabolized by hepatic cytochrome P450 (CYP450) and converted to intermediate metabolites. Adapted from Zhang Y, Li M, Tang J and Chen X. Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives. Int. J. Environ. Res. Public Health³³ 307–316, Copyright 2011, with permission from Elsevier.³⁴

Legrand D, Barbato E, Chenu P, et al. The STIB score: a simple clinical test to predict clopidogrel resistance. Acta Cardiol. 2015;70(5):516–521.

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Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011;305(11):1097–1105.

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Zhang Y, Li M, Tang J and Chen X. 2017. Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives. Int. J. Environ. Res. Public Health. 14(3): 301.10.3390/ijerph14030301

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Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res. 2011;128:307–316.

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