title: POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia.
abstract: BACKGROUND
  In children and adolescents with familial hypercholesterolemia (FH) pharmacotherapy with statins is the cornerstone in the current regimen to reduce low-density lipoprotein cholesterol (LDLc) and premature coronary heart disease risk. There is, however, a great interindividual variation in response to therapy, partially attributed to genetic factors. The polymorphic enzyme POR transfers electrons from NADPH to CYP450 enzymes including CYP3A, which metabolize atorvastatin. POR*28 polymorphism is associated with increased CYP3A enzyme activity. We analyzed the association of POR*28 allele with response to atorvastatin.
  
  
  METHODS
  One hundred and five FH children and adolescents treated with atorvastatin at doses 10-40 mg were included in the study. Total cholesterol (TChol) and LDLc were measured at baseline and after 6 months of treatment. POR*28 allele was analyzed with TaqMan assay. CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G genotypes were also determined with TaqMan or PCR-RFLP methods.
  
  
  RESULTS
  POR*28 carriers had significantly lower percent mean reduction of TChol (33.1% in *1/*1, 29.8% in *1/*28 and 25.9% in *28/*28 individuals, p = 0.045) and of LDLc (43.9% in *1/*1, 40.9% in *1/*28 and 30.8% in *28/*28 individuals, p = 0.013). In multivariable linear regression adjusted for confounding factors, POR*28 genotypes, additionally to baseline cholesterol level, accounted for an estimated 8.3% and 7.3% of overall variability in % TChol and LDLc reduction (β: 4.05; 95% CI: 1.73-6.37; p = 0.001 and β: 5.08; 95% CI: 1.62-8.54; p = 0.004, respectively). CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G polymorphisms were not associated with lipid reductions and did not modify the effect of POR*28 on atorvastatin response.
  
  
  CONCLUSIONS
  In children with FH, carriage of POR*28 allele is associated with reduced effect of atorvastatin on TChol and LDLc and therefore identifies FH children that may require higher atorvastatin doses to achieve full therapeutic benefits. Additional studies in different populations are needed to replicate this association.
authors.affiliation: Unit of Metabolic Diseases, 1st Department of Pediatrics, Choremio Research Laboratory, Aghia Sophia Children's Hospital, Medical School, University of Athens, Athens, Greece.
authors.forename: Euridiki
authors.initials: E
authors.lastname: Drogari
authors.forename: Georgia
authors.initials: G
authors.lastname: Ragia
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Mollaki
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Ron H N
authors.initials: RH
authors.lastname: Van Schaik
authors.forename: Vangelis G
authors.initials: VG
authors.lastname: Manolopoulos
mesh_terms: D000293:Adolescent; D000483:Alleles; D000069059:Atorvastatin; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D008297:Male; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000008:administration & dosage*; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D006538:Heptanoic Acids; C573412:LDLR protein, human; D008077:Lipoproteins, LDL; D011758:Pyrroles; D011973:Receptors, LDL; D000069059:Atorvastatin; D009251:NADPH-Ferrihemoprotein Reductase
keywords: P450 oxidoreductase; POR*28; atorvastatin; children; hypercholesterolemia; pharmacogenomics