CYP3A4, CYP3A5, and CYP4F2 Polymorphisms and Bleeding Risk in Ticagrelor-Based Dual Antiplatelet Therapy

Area of Science:

• Pharmacogenomics
• Cardiovascular Medicine
• Clinical Chemistry

Background:

• Ticagrelor is crucial for acute coronary syndrome (ACS) but increases bleeding risk.
• Predicting ticagrelor-induced bleeding is vital, yet the role of specific cytochrome P450 (CYP450) gene polymorphisms remains unclear.
• This study investigates CYP3A4*22, CYP3A5*3, and CYP4F2 variants' association with bleeding in ACS patients.

Purpose of the Study:

• To assess the association between CYP3A4*22, CYP3A5*3, and CYP4F2 genetic variants and bleeding events in Serbian ACS patients receiving ticagrelor.
• To determine if these genetic polymorphisms improve bleeding risk prediction beyond established clinical factors.

Main Methods:

• Prospective observational study of 105 ACS patients receiving dual antiplatelet therapy (DAPT) with ticagrelor.
• Bleeding events classified using Bleeding Academic Research Consortium (BARC) criteria.
• Genotyping performed using TaqMan assays; association analysis with Firth's penalized logistic regression and machine learning (XGBoost with SHAP).

Main Results:

• Advanced age (≥75 years) and impaired renal function (eGFR <60 mL/min/1.73 m²) were the strongest clinical predictors of bleeding.
• CYP3A5*1 carrier status showed a univariable association with bleeding, but this was explained by older age and poorer renal function in carriers.
• No significant association was found between CYP3A4*22, CYP3A5*3, or CYP4F2 variants and major bleeding events (BARC 3/5).

Conclusions:

• Clinical factors, particularly age and renal function, are the primary drivers of bleeding risk in ACS patients treated with ticagrelor.
• The observed association with CYP3A5*1 was confounded by baseline clinical characteristics.
• Preemptive genotyping for CYP3A4*22, CYP3A5*3, and CYP4F2 is unlikely to enhance bleeding risk assessment beyond standard clinical evaluation.