title: Do MDR1 and SLCO1B1 polymorphisms influence the therapeutic response to atorvastatin? A study on a cohort of Egyptian patients with hypercholesterolemia.
abstract: BACKGROUND
  Statins are among the most prescribed drugs worldwide to reduce the risk of cardiovascular events. Interindividual variability in drug response is a major clinical problem and is of concern during drug development. Statins, such as atorvastatin, are taken orally and access to their site of action in the liver is greatly facilitated by both intestinal and hepatic transporters.
  
  
  OBJECTIVE
  To examine the impact of polymorphisms of the multidrug resistance 1(MDR1) and solute carrier organic anion transporter 1B1 (SLCO1B1) genes on the therapeutic response to atorvastatin as well as the presence of gender-gene interaction.
  
  
  METHODS
  Serum lipid levels were determined at baseline and 4 weeks following 40 mg/day atorvastatin treatment in 50 Egyptian hypercholesterolemic patients (27 males and 23 females). Identification of MDR1 C3435T and SLCO1B1 A388G gene polymorphisms was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.
  
  
  RESULTS
  Treatment with atorvastatin resulted in a mean reduction of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) of 8.7 %, 9.2 %, and 4.1 %, respectively, and a mean increase of high density lipoprotein cholesterol (HDL-C) of 1 %. Baseline and post-treatment HDL-C levels were statistically significantly higher in the MDR 1 TT homozygotes when compared with the CC wild type. The percentage change in TC, LDL-C, TG, and HDL-C did not show any statistically significant difference when compared among the different MDR 1 C3435T or SLCO1B1 A388G genotypes. The SLCO1B1 GG homozygotes showed a decrease in TG, whereas there was an increase in TG following atorvastatin treatment in AA and AG carriers in females; however, males did not show any statistically significant difference. There was no statistically significant association between either the coronary artery disease (CAD) risk factors (family history of CAD, hypertension, diabetes mellitus, smoking) or concomitant medications with the percentage change in different lipid parameters.
  
  
  CONCLUSIONS
  MDR1 C3435T was associated with baseline and post-treatment HDL-C variation. SLCO1B1 A388G showed gender-related effects on TG change following atorvastatin treatment. None of the comorbidities or the concomitant medications influenced the percentage change of lipid parameters following atorvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipid response to atorvastatin treatment.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Fayoum University, Fayoum, Egypt.
authors.forename: Mona F
authors.initials: MF
authors.lastname: Shabana
authors.forename: Amal A
authors.initials: AA
authors.lastname: Mishriki
authors.forename: Marianne Samir M
authors.initials: MS
authors.lastname: Issac
authors.forename: Sameh W G
authors.initials: SW
authors.lastname: Bakhoum
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000069059:Atorvastatin; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004534:Egypt; D005260:Female; D014644:Genetic Variation; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D012307:Risk Factors; D012727:Sex Characteristics; D014280:Triglycerides / Q000097:blood
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011758:Pyrroles; C503999:SLCO1B1 protein, human; D014280:Triglycerides; D000069059:Atorvastatin