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rs4148323 A等位基因与中国冠心病患者2-羟基阿托伐他汀生成增加及更高死亡风险相关。

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

作者信息

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

机构信息

Research Center of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangzhou, China.

出版信息

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

DOI:10.3389/fphar.2021.586973
PMID:33762934
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7982952/
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 () showed an increase in 2-hydroxy ATV/ATV ratio ( = 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 ( = 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; = 0.0198). In conclusion, our results suggested that the rs4148323 A allele was associated with increased 2-hydroxy ATV formation and was a significant death risk factor in Chinese patients with CAD.

摘要

人们普遍认为，基因多态性会影响阿托伐他汀（ATV）的代谢、临床疗效和不良事件。本研究的目的是在中国冠心病（CAD）患者中鉴定影响ATV代谢和转归的新基因变异。共纳入1079例CAD患者并随访5年。使用全球筛选阵列-24 v1.0芯片或人类全基因组中华8芯片对血液和人肝组织样本的DNA进行基因分型。采用经过验证的超高效液相色谱质谱联用（UPLC-MS/MS）方法测定血浆和肝脏样本中ATV及其代谢产物的浓度。携带rs4148323多态性（）A等位基因的患者相对于无变异等位基因个体，其2-羟基阿托伐他汀/阿托伐他汀比值升高（ = 1.69E-07，错误发现率[FDR] = 8.66E-03）。该结果在另外222例CAD患者组成的独立队列中得到进一步验证（ = 1.08E-07）。此外，rs4148323 A等位基因与死亡风险增加相关（风险比[HR] 1.774；95%置信区间[CI]，1.031 - 3.052； = 0.0198）。总之，我们的结果表明，rs4148323 A等位基因与2-羟基阿托伐他汀生成增加相关，是中国CAD患者的一个显著死亡风险因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/d14c6d905b6b/fphar-12-586973-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/a7ef9ad15486/fphar-12-586973-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/3152437d3298/fphar-12-586973-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/0cb95b515511/fphar-12-586973-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/d14c6d905b6b/fphar-12-586973-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/a7ef9ad15486/fphar-12-586973-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/3152437d3298/fphar-12-586973-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/0cb95b515511/fphar-12-586973-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9cf4/7982952/d14c6d905b6b/fphar-12-586973-g004.jpg

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