细胞色素 P450 3A4*22 和 3A5*3 基因型和多态性与高胆固醇血症患者对辛伐他汀反应的相关性。
Association of cytochromes P450 3A4*22 and 3A5*3 genotypes and polymorphism with response to simvastatin in hypercholesterolemia patients.
机构信息
Department of Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
出版信息
PLoS One. 2022 Jul 15;17(7):e0260824. doi: 10.1371/journal.pone.0260824. eCollection 2022.
BACKGROUNDS
Inter-individual variability in response to statin was mainly due to genetic differences. This study aimed to investigate the association of CYP3A422 (rs35599367), CYP3A53 (rs776746) single nucleotide polymorphism (SNP) with response to simvastatin in hypercholesterolemia patients conducted at King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia.
PATIENTS AND METHODS
A total of 274 participants were registered in the current study. Hypercholesterolemic patients taking simvastatin 20 mg (n = 148) and control subjects (n = 126) were tested for rs35599367 and rs776746 genotypes using Custom Taqman ® Assay Probes. Response to simvastatin in these patients was assessed by determination of low density lipoprotein (LDL-C), total cholesterol (TC) and by measuring statin plasma levels using Liquid Chromatography-Mass Spectrometry (LC-MS).
RESULTS
None of the participants carried a homozygous CYP3A422 mutant genotype, while 12 (4.4%) individuals had a heterozygous genotype and 262 (95.6%) had a wild homozygous genotype. The CYP3A53 allele was detected in the homozygous mutant form in 16 (5.8%) individuals, while 74 (27.0%) individuals carried the heterozygous genotype and 184 (67.2%) carried the wildtype homozygous genotype. Of the patient group, 15 (11%) were classified as intermediate metabolizers (IMs) and 133 (89%) as extensive metabolizers (EMs). Plasma simvastatin concentrations for the combined CYP3A4/5 genotypes were significantly (P<0.05) higher in the IMs group than in the EMs group. TC and plasma LDL-C levels were also significantly (P<0.05) higher in IMs than in EMs.
CONCLUSION
The present study showed associations between CYP3A422 (rs35599367) and CYP3A53 (rs776746) SNP combination genotypes with response to statins in hypercholesterolemia. Patients who had either a mutant homozygous allele for CYP3A53 or mutant homozygous and heterozygous alleles for CYP3A422 showed increased response to lower TC and LDL-C levels.
背景
他汀类药物反应的个体间差异主要归因于遗传差异。本研究旨在探讨 CYP3A422（rs35599367）和 CYP3A53（rs776746）单核苷酸多态性（SNP）与沙特阿拉伯吉达阿卜杜勒阿齐兹国王大学医院（KAUH）接受辛伐他汀治疗的高胆固醇血症患者对辛伐他汀反应的相关性。
方法
本研究共登记了 274 名参与者。接受辛伐他汀 20mg 治疗的高胆固醇血症患者（n=148）和对照组（n=126）使用定制 Taqman®Assay Probes 检测 rs35599367 和 rs776746 基因型。通过测定低密度脂蛋白（LDL-C）、总胆固醇（TC）和使用液相色谱-质谱法（LC-MS）测量他汀类药物的血浆水平来评估这些患者对辛伐他汀的反应。
结果
无参与者携带纯合 CYP3A422 突变基因型，12 名（4.4%）个体携带杂合基因型，262 名（95.6%）个体携带野生型纯合基因型。CYP3A53 等位基因以纯合突变形式在 16 名（5.8%）个体中检出，74 名（27.0%）个体携带杂合基因型，184 名（67.2%）个体携带野生型纯合基因型。在患者组中，15 名（11%）被归类为中间代谢者（IMs），133 名（89%）为广泛代谢者（EMs）。联合 CYP3A4/5 基因型的辛伐他汀血浆浓度在 IM 组显著高于 EMs 组（P<0.05）。TC 和血浆 LDL-C 水平在 IMs 组也显著高于 EMs 组（P<0.05）。
结论
本研究表明 CYP3A422（rs35599367）和 CYP3A53（rs776746）SNP 组合基因型与高胆固醇血症患者对他汀类药物的反应相关。CYP3A53 纯合突变等位基因或 CYP3A422 纯合突变和杂合突变等位基因的患者对 TC 和 LDL-C 水平的降低有更高的反应。
Zotero 插件