Abstract
Atorvastatin is commonly used among type 2 diabetic (DM2) patients at the University of Jordan Hospital to prevent cardiovascular complication. However, we noticed that there is a wide inter-individual variation in the efficacy and toxicity of atorvastatin. This study aimed to find out the effects of major genetic variants in 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), Apolipoprotein E (APOE), and Solute Carrier Organic Anion (SLCO1B1) genes on atorvastatin response among DM2 patients. A sample of 139 DM2 patients on 20 mg of atorvastatin was included in this study. The lipid and glycemic profile and the levels of hepatic enzymes alanine aminotransferase (ALT) and aspartate transaminase were recorded before and after 3 months of atorvastatin treatment. Additionally, the genetic variants HMGCR rs17244841, APOE rs7412 and rs429357, and SLCO1B1 rs2306283 and rs11045818 were genotyped using an Applied Biosystems DNA sequencing method (ABI3730×1). We found that atorvastatin reduced total cholesterol and low-density lipoprotein (LDL) more significantly (p-value < 0.05) in patients with wild genotype than variant alleles APOE rs7412C > T and SLCO1B1 rs2306283A > G. Furthermore, the ALT level was elevated significantly (p-value < 0.05) by 27% in patients with heterozygous SLCO1B1 rs11045818 G/A genotype, while it was not elevated among wild genotype carriers. Additionally, atorvastatin reduced total cholesterol more significantly (p-value < 0.05) in patients with SLCO1B1 rs2306283A and rs11045818G haplotypes and increased ALT levels by 27% (p-value < 0.05) in patients with SLCO1B1 rs2306283G and rs11045818A haplotypes. In conclusion, it was found in this study that APOE rs7412, SLCO1B1 rs2306283, and rs11045818 genotypes can be considered as potential genetic biomarkers of atorvastatin response among DM2 patients of Jordanian Arabic origin. Further clinical studies with larger sample numbers are needed to confirm these findings.
Highlights
Atorvastatin is a strong, long-acting inhibitor of 3-hydroxy glutaryl co-enzyme A reductase (HMGCR), which is the rate-limiting step in the biosynthesis of cholesterol [1]
We found that Solute carrier organic anion 1B1 (SLCO1B1) rs2306283 and rs11045818 haplotypes are associated with total cholesterol and alanine aminotransferase (ALT) blood level alterations induced by atorvastatin treatment (Table 6)
We showed that the Apolipoprotein E (APOE) rs7412 T allele decreased the atorvastatin response, and APOE rs7412 C/T genotype DM2 patients had a significantly lower response to atorvastatin
Summary
Atorvastatin is a strong, long-acting inhibitor of 3-hydroxy glutaryl co-enzyme A reductase (HMGCR), which is the rate-limiting step in the biosynthesis of cholesterol [1]. Atorvastatin is used widely in the treatment of hypercholesterolemia [2]. Association of Diabetes recommend using statin drugs for the prevention of cardiovascular complication of diabetes mellitus (DM) [3]. Physicians at the University of Jordan Hospital prescribe statins, especially atorvastatin, to DM2 patients. There is an inter-individual variation in the atorvastatin response. Some patients still have high cholesterol levels even when they are on statin treatment, and some patients suffer from statin-induced hepatotoxicity and myopathy [4]
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