An in silico model of aspirin-iduced inactivation of platelet and Megakaryocyte Cyclooxygenase-1

Abstract

August 2015 e7 Alexandroupolis, Greece; University of Athens Medical School, Aghia Sophia Children’s Hospital, Athens, Greece; Erasmus Medical Center, Rotterdam, The Netherlands; and Catholic University of Louvain, Brussels, Belgium Introduction: 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. It has been suggested that genetic polymorphism of the enzymes POR, CYP3A4, CYP3A5 and solute carrier SLCO1B1 may influence this variation. We analyzed the association of alleles POR*28, CYP3A4*22, CYP3A5*3, and SLCO1B1 521T> C and 388A> G with response to atorvastatin. Methods: The study included 105 FH children and adolescents treated with atorvastatin (10 to 40 mg). Total cholesterol (TChol) and LDLc were measured at baseline and after 6 months of treatment. POR*28 CYP3A4*22, and CYP3A5*3 alleles and SLCO1B1 521T> C and 388A> G genotypes were 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 LDL-c (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, account for an estimated 8.3% and 7.3% of overall variability in percent 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 was associated with reduced effect of atorvastatin on TChol and LDLc and therefore identifies FH children who may require higher atorvastatin doses to achieve full therapeutic benefits. Further studies in different populations are needed to replicate the association.