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. 2022 Feb 17:15:119-130.
doi: 10.2147/PGPM.S346093. eCollection 2022.

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

Natchaya Vanwong  1   2 , Sayanit Tipnoppanon  1 , Chalitpon Na Nakorn  3 , Pornpen Srisawasdi  4 , Punyanuch Rodcharoen  4 , Sadeep Medhasi  5 , Pajaree Chariyavilaskul  2   6   7 , Sarawut Siwamogsatham  2   8   9 , Yongkasem Vorasettakarnkij  2   9 , Chonlaphat Sukasem  10   11   12
Affiliations

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

Natchaya Vanwong et al. Pharmgenomics Pers Med. .

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; SLCO1B3 (rs4149117, rs7311358, and rs2053098), QPRT (rs13331798), and SLC10A2 (rs188096) showed a suggestive association with LDL-cholesterol-lowering response. HDL-cholesterol-lowering responses were found to be related to CYP7A1 gene variant (rs12542233). Seven variants, SLCO1B3 (rs4149117, rs7311358, and rs2053098); SULT1E1 (rs3736599 and rs3822172); and ABCB11 (rs4148768 and rs3770603), were associated with the total cholesterol-lowering response. One variant of the ABCB4 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.

Keywords: drug transporters; drug-metabolizing enzymes; gene polymorphisms; statin.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Manhattan plot of – log10 (P-values) from Cochran–Armitage test for trends of 419 single nucleotide polymorphisms (SNPs) in drug-metabolizing enzyme and transporter (DMET) genes and percentage changes in LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), total cholesterol (TC), and triglyceride (TG) levels. The X-axis indicates chromosome number and Y-axis indicates -log10P-values. The green line indicates a P-value of 0.01. The black line indicates a P-value of 2.5×10−5. (A) Manhattan plot demonstrates the significant DMET SNPs associated with the percentage change in LDL-cholesterol (B) Manhattan plot demonstrates the significant DMET SNPs associated with the percentage change in HDL-cholesterol (C) Manhattan plot demonstrates the significant DMET SNPs associated with the percentage change in total cholesterol and (D) Manhattan plot demonstrates the significant DMET SNPs associated with the percentage change in triglyceride.
Figure 2
Figure 2
Haploview linkage disequilibrium map of SNPs across DMET genes: (A) SLCO1B3; (B) ABCB11; and (C) SULT1E1. Pairwise linkage disequilibrium (D’) values are given in blocks for each SNP combination. Empty dark red blocks indicate D’ values of 1.0.
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