UGT1A1 rs4148323 A Allele is Associated With Increased 2-Hydroxy Atorvastatin Formation and Higher Death Risk in Chinese Patients With Coronary Artery Disease

He-Ping Lei; Min Qin; Li-Yun Cai; Hong Wu; Lan Tang; Ju-E Liu; Chun-Yu Deng; Yi-Bin Liu; Qian Zhu; Han-Ping Li; Wei Hu; Min Yang; Yi-Zhun Zhu; Shi-Long Zhong

doi:10.3389/fphar.2021.586973

UGT1A1 rs4148323 A Allele is Associated With Increased 2-Hydroxy Atorvastatin Formation and Higher Death Risk in Chinese Patients With Coronary Artery Disease

Front Pharmacol. 2021 Mar 8:12:586973. doi: 10.3389/fphar.2021.586973. eCollection 2021.

Authors

He-Ping Lei^{1

2

3}, Min Qin^{1

2

4}, Li-Yun Cai^{1

2

5}, Hong Wu⁶, Lan Tang⁵, Ju-E Liu⁷, Chun-Yu Deng^{1

2}, Yi-Bin Liu^{1

2}, Qian Zhu^{1

2}, Han-Ping Li^{1

2}, Wei Hu³, Min Yang^{1

2}, Yi-Zhun Zhu³, Shi-Long Zhong^{1

2

4

7}

Affiliations

¹ Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
² Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.
³ School of Pharmacy, Macau University of Science and Technology, Macau, China.
⁴ School of Medicine, South China University of Technology, Guangzhou, China.
⁵ School of Pharmacy, Southern Medical University, Guangzhou, China.
⁶ Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
⁷ Department of Pharmacy, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

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.

Keywords: ADME genes; UGT1A1∗6; atorvastatin; clinical outcomes; coronary artery disease; polymorphisms.