Prevalence of risk phenotypes associated with CYP2C9*2, *3 and VKORC1 c.-1639G>A genetic polymorphisms in the world populations: Implications in clinical practice

Dr. Mohitosh Biswas^1*Murshadul Alam Murad¹Maliheh Ershadian²Most. Sumaiya Khatun Kali³Maw Shin Sim⁴Baharudin Ibrahim⁵CHONLAPHAT SUKASEM²

• ¹Department of Pharmacy, University of Rajshahi, Rajshahi, Bangladesh
• ²Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
• ³Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Dhaka, Bangladesh
• ⁴Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
• ⁵6Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Malaysia, Kuala Lumpur, Malaysia

The safety or efficacy of drugs may be affected by the genetic variability of CYP2C9 or VKORC1. Patients may be at elevated risks of drug-related toxicities i.e. bleeding toxicity if they carry CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), or VKORC1 c.-1639G>A (rs9923231) genetic variants. Methods: Allele frequency of CYP2C9*2, *3 and VKORC1 c.-1639G>A were obtained from the 1000 Genomes Project Phase III in line with Fort Lauderdale principles. Predictive risk phenotypes and correlations were assigned based on the carrying of characteristic allele carriers following international pharmacogenomics (PGx)-based dosing guidelines. Results: Intermediate and poor metabolizers were predicted to be risk phenotypes (17.8%; 95% CI 16.3-19.3%) due to inheriting CYP2C9*2 and *3 genetic variants and these risk phenotypes were highest in the Europeans (35%; 95% CI 30.8-39.2%), followed by South Asians (26.8%; 95% CI 22.9-30.7%), Americans (25.9%; 95% CI 21.3-30.5%), East Asians (6.7%; 95% CI 4.5-8.9%) and African population (2.1%; 95% CI 1-3.2%). Also, sensitive and highly sensitive responders were considered risk phenotypes (33.1%; 95% CI 31.3-35%) when combining CYP2C9*2, *3 variants with VKORC1c.-1639G>A and these risk phenotypes were prevalent highest in East Asia (79.6%; 95% CI 76-83.1%), followed by European (38.6%; 95% CI 34.3-42.8%), American (30%; 95% CI 25.2-34.8%), South Asian (25.2%; 95% CI 21.3-29%), and African population (1.2%; 95% CI 0.4-2%), respectively. The prevalence of risk phenotypes in different ethnic groups was statistically significant (p<0.05; 1.94×10 -175 , χ 2 test). According to clinical annotations in the PharmGKB, the safety or efficacy of at least 29 commonly prescribed drugs is impacted by the genetic polymorphisms of CYP2C9/ VKORC1 c.-1639G>A in varying degrees. The PGx-label information is available for at least 23 drugs, and CPIC has already recomended PGx-based dosing guidelines for at least 11 of these medications, based on the genetic variability of CYP2C9/ VKORC1 c.-1639G>A. Conclusion: To enhance the safety of at least 11 clinically significant drugs, the current study found that approximately one-fifth of the global population is at risk based on the CYP2C9*2 and *3 genotypes. Additionally, about one-third of the population is at risk when considering the combination of CYP2C9 and VKORC1 c.-1639G>A genotypes.