Association of Drug-Metabolizing Enzyme and Transporter Gene Polymorphisms and Lipid-Lowering Response to Statins in Thai Patients with Dyslipidemia

Overview

Journal Pharmgenomics Pers Med

Publisher Dove Medical Press

Date 2022 Feb 25

PMID 35210819

Authors

Natchaya Vanwong

Sayanit Tipnoppanon

Chalitpon Na Nakorn

Pornpen Srisawasdi

Punyanuch Rodcharoen

Sadeep Medhasi

Pajaree Chariyavilaskul

Sarawut Siwamogsatham

Yongkasem Vorasettakarnkij

Chonlaphat Sukasem

Affiliations

Soon will be listed here.

Abstract

Purpose: Statins are increasingly widely used in the primary and secondary prevention of cardiovascular disease. However, there is an inter-individual variation in statin response among patients. The study aims to determine the association between genetic variations in drug-metabolizing enzyme and transporter (DMET) genes and lipid-lowering response to a statin in Thai patients with hyperlipidemia.

Patients And Methods: Seventy-nine patients who received statin at steady-state concentrations were recruited. Serum lipid profile was measured at baseline and repeated after 4-month on a statin regimen. The genotype profile of 1936 DMET markers was obtained using Affymetrix DMET Plus genotyping microarrays.

Results: In this DMET microarray platform, five variants; (rs4149117, rs7311358, and rs2053098), (rs13331798), and (rs188096) showed a suggestive association with LDL-cholesterol-lowering response. HDL-cholesterol-lowering responses were found to be related to gene variant (rs12542233). Seven variants, (rs4149117, rs7311358, and rs2053098); (rs3736599 and rs3822172); and (rs4148768 and rs3770603), were associated with the total cholesterol-lowering response. One variant of the gene (rs2109505) was significantly associated with triglyceride-lowering response.

Conclusion: This pharmacogenomic study identifies new genetic variants of DMET genes that are associated with the lipid-lowering response to statins. Genetic polymorphisms in DMET genes may impact the pharmacokinetics and lipid-lowering response to statin. The validation studies confirmations are needed in future pharmacogenomic studies.

References

McGraw J, Waller D . Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol. 2012; 8(3):371-82. DOI: 10.1517/17425255.2012.657626. View

Sticova E, Jirsa M . ABCB4 disease: Many faces of one gene deficiency. Ann Hepatol. 2019; 19(2):126-133. DOI: 10.1016/j.aohep.2019.09.010. View

Yang J, Hao J, Wang S, Zhu Z, Fang Q, Bao H . Association between the LXRα polymorphism and stroke in a Chinese population. Genet Mol Res. 2015; 14(1):1757-62. DOI: 10.4238/2015.March.13.2. View

Taylor F, Huffman M, Macedo A, Moore T, Burke M, Davey Smith G . Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013; (1):CD004816. PMC: 6481400. DOI: 10.1002/14651858.CD004816.pub5. View

Arbitrio M, Di Martino M, Scionti F, Agapito G, Guzzi P, Cannataro M . DMET™ (Drug Metabolism Enzymes and Transporters): a pharmacogenomic platform for precision medicine. Oncotarget. 2016; 7(33):54028-54050. PMC: 5288240. DOI: 10.18632/oncotarget.9927. View

Letschert K, Keppler D, Konig J . Mutations in the SLCO1B3 gene affecting the substrate specificity of the hepatocellular uptake transporter OATP1B3 (OATP8). Pharmacogenetics. 2004; 14(7):441-52. DOI: 10.1097/01.fpc.0000114744.08559.92. View

Willrich M, Hirata M, Genvigir F, Arazi S, Rebecchi I, Rodrigues A . CYP3A53A allele is associated with reduced lowering-lipid response to atorvastatin in individuals with hypercholesterolemia. Clin Chim Acta. 2008; 398(1-2):15-20. DOI: 10.1016/j.cca.2008.07.032. View

Hirano M, Maeda K, Hayashi H, Kusuhara H, Sugiyama Y . Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther. 2005; 314(2):876-82. DOI: 10.1124/jpet.105.084830. View

Fruchart J . Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis. 2009; 205(1):1-8. DOI: 10.1016/j.atherosclerosis.2009.03.008. View

10.

Gu G, Xu X, Yang Q, Zeng R . Effect of CETP polymorphism on atorvastatin lipid-regulating effect and clinical prognosis of patients with coronary heart disease. Med Sci Monit. 2014; 20:2824-9. PMC: 4285921. DOI: 10.12659/MSM.892711. View

11.

Pan W, Song I, Shin H, Kim M, Choi Y, Lim S . Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations. Xenobiotica. 2011; 41(6):501-10. DOI: 10.3109/00498254.2011.555567. View

12.

Dean M, Rzhetsky A, Allikmets R . The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001; 11(7):1156-66. DOI: 10.1101/gr.184901. View

13.

Zhou Y, Zhang J, Li Z, Miao J, Yin Q, Li J . Association of liver X receptor α (LXRα) gene polymorphism and coronary heart disease, serum lipids and glucose levels. Lipids Health Dis. 2014; 13:34. PMC: 3975963. DOI: 10.1186/1476-511X-13-34. View

14.

Shah S, Yoon G, Chung S, Abid M, Kim T, Lee H . Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer's disease neuropathological deficits. Mol Psychiatry. 2016; 22(3):407-416. PMC: 5322276. DOI: 10.1038/mp.2016.23. View

15.

Marschall H, Katsika D, Rudling M, Einarsson C . The genetic background of gallstone formation: an update. Biochem Biophys Res Commun. 2010; 396(1):58-62. DOI: 10.1016/j.bbrc.2010.02.143. View

16.

Gao Y, Zhang L, Fu Q . CYP3A4*1G polymorphism is associated with lipid-lowering efficacy of atorvastatin but not of simvastatin. Eur J Clin Pharmacol. 2008; 64(9):877-82. DOI: 10.1007/s00228-008-0502-x. View

17.

Na Nakorn C, Waisayarat J, Dejthevaporn C, Srisawasdi P, Wongwaisayawan S, Sukasem C . Genetic Variations and Frequencies of the Two Functional Single Nucleotide Polymorphisms of in the Thai Population. Front Pharmacol. 2020; 11:728. PMC: 7289979. DOI: 10.3389/fphar.2020.00728. View

18.

Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F . SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004; 86(11):839-48. DOI: 10.1016/j.biochi.2004.09.018. View

19.

Hubacek J, Bobkova D . Role of cholesterol 7alpha-hydroxylase (CYP7A1) in nutrigenetics and pharmacogenetics of cholesterol lowering. Mol Diagn Ther. 2006; 10(2):93-100. DOI: 10.1007/BF03256448. View

20.

Romani M, Hofer D, Katsyuba E, Auwerx J . Niacin: an old lipid drug in a new NAD dress. J Lipid Res. 2019; 60(4):741-746. PMC: 6446705. DOI: 10.1194/jlr.S092007. View