Genetic polymorphism of CYP3A4 associated with reduced response to statin therapy in Pakistani cardiac and dyslipidemic patients: A cross-sectional observational study

Background: Drug resistance phenomenon has become a serious problem in the lipid lowering drugs in the treatment of cardiac and dyslipidemic patients. Statins are the mainstay pharmacological treatment for dyslipidemia, metabolized by CYP3A4 gene. CYP3A4 genetic variants are involved in statins resistance, of which CYP3A4*4 and CYP3A4*1G has been observed as important loss of function alleles. Objectives: The current study aimed to investigate the CYP3A4 (CYP3A4*4 and CYP3A4*1G) polymorphisms, their association with lipid parameters and influence of variations in response to statin drugs. Methods: This cross-sectional observational study included 100 cardiac and dyslipidemic patients receiving statin therapy at Mayo Hospital Lahore, Pakistan. Biochemical assays were performed for lipid parameters and genotyping of CYP3A4 (CYP3A4*4 and CYP3A4*1G) variants by using allele specific polymerase chain reaction (AS-PCR) technique. The amplicons of identified variants were electrophoresed and results were verified through Sanger sequencing. Results: Serum lipid profile of selected patients presented higher values of total cholesterol (TC) in 51% individuals, total triglycerides (TG) in 79%, LDL- cholesterol in 46% and HDL- cholesterol in 17%. Observed genotypes for CYP3A4*4 and CYP3A4*1G in selected patients included homozygous wild type, homozygous mutant type, heterozygous bi- allelic, as well as tri and tetra- allelic patterns representing multi-locus haplotype combinations. Statistical analysis was performed using SPSS version 27.0. Significant correlations were observed between lipid parameters, whereas CYP3A4 variants showed modest associations with lipid parameters in studied population. Conclusion: The study provides significant inter racial genetic variations in CYP3A4*4 and CYP3A4*1G in studied population, which might be responsible for the variable response of statins in cardiac and dyslipidemic patients. Although the study addresses the main question about pharmaco-genetic in studied population, the observed genotype–phenotype associations are limited and should be interpreted carefully, emphasizing on the need for additional validation in larger population.