Abstract
It is widely accepted that genetic polymorphisms impact atorvastatin (ATV) metabolism, clinical efficacy, and adverse events. The objectives of this study were to identify novel genetic variants influencing ATV metabolism and outcomes in Chinese patients with coronary artery disease (CAD). A total of 1079 CAD patients were enrolled and followed for 5 years. DNA from the blood and human liver tissue samples were genotyped using either Global Screening Array-24 v1.0 BeadChip or HumanOmniZhongHua-8 BeadChip. Concentrations of ATV and its metabolites in plasma and liver samples were determined using a verified ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) method. The patients carrying A allele for the rs4148323 polymorphism (UGT1A1) showed an increase in 2-hydroxy ATV/ATV ratio (p = 1.69E−07, false discovery rate [FDR] = 8.66E−03) relative to the value in individuals without the variant allele. The result was further validated by an independent cohort comprising an additional 222 CAD patients (p = 1.08E−07). Moreover, the rs4148323 A allele was associated with an increased risk of death (hazard ratio [HR] 1.774; 95% confidence interval [CI], 1.031–3.052; p = 0.0198). In conclusion, our results suggested that the UGT1A1 rs4148323 A allele was associated with increased 2-hydroxy ATV formation and was a significant death risk factor in Chinese patients with CAD.
Highlights
Atorvastatin (ATV), which reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, is among the most widely prescribed drugs for treating and preventing atherosclerotic disease events (Rosenson, 2006)
Univariate linear regression analysis indicated that patients with older age, higher ATV dose, higher levels of alanine aminotransferase (ALT), AST, CREA, CHOL and LDL-C tended to have a higher plasma ATV concentration, while patients with higher levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (a) [Apo (a)] tended to have a lower plasma ATV concentration
Further analysis indicated that rs4148323 was in strong linkage disequilibrium (LD) with rs3806598, and rs15524 was in strong LD with the remaining seven loci located in chromosome 7 (r2 > 0.5)
Summary
Atorvastatin (ATV), which reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase, is among the most widely prescribed drugs for treating and preventing atherosclerotic disease events (Rosenson, 2006). ATV is orally administered in the active acid form and is extensively metabolized by cytochrome P450 (CYP) 3A4 to form two major active metabolites, 2-hydroxy (2-OH) ATV and 4hydroxy (4-OH) ATV (Park et al, 2008). Both metabolites are pharmacologically equivalent to parent ATV and significantly contribute to the circulating inhibitory activity for HMG-CoA reductase (Lennernas 2003).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
