title: Impact of variants within seven candidate genes on statin treatment efficacy.
abstract: Statins are the most commonly used drugs in patients with dyslipidemia. Among the patients, a significant inter-individual variability with supposed strong genetic background in statin treatment efficacy has been observed. Genome wide screenings detected variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes that are among the candidates potentially modifying response to statins. Ten variants (SNPs) within these genes (rs599838, rs646776, rs16996148, rs693, rs515135, rs4420638, rs12654264, rs6511720, rs6235, rs11206510) were analyzed in 895 (46 % men, average age 60.3+/-13.1 years) patients with dyslipidemia treated with equipotent doses of statins (~90 % on simvastatin or atorvastatin, doses 10 or 20 mg) and selected 672 normolipidemic controls (40 % men, average age 46.5 years). Lipid parameters were available prior to the treatment and after 12 weeks of therapy. Statin treatment resulted in a significant decrease of both total cholesterol (7.00+/-1.53-->5.15+/-1.17 mmol/l, P<0.0001) and triglycerides (2.03+/-1.01-->1.65+/-1.23 mmol/l, P<0.0005). Rs599838 variant was not detected in first analyzed 284 patients. After adjustment for multiple testing, there was no significant association between individual SNPs and statin treatment efficacy. Only the rs4420638 (APOE/C1/C4 gene cluster) G allele carriers seem to show more profitable change of HDL cholesterol (P=0.007 without and P=0.06 after adjustment). Results demonstrated that, although associated with plasma TC and LDL cholesterol per se, variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes do not modify therapeutic response to statins.
authors.affiliation: Third Department of Internal Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic. michal.vrablik@vfn.cz
authors.forename: M
authors.initials: M
authors.lastname: Vrablík
authors.forename: J A
authors.initials: JA
authors.lastname: Hubáček
authors.forename: D
authors.initials: D
authors.lastname: Dlouhá
authors.forename: V
authors.initials: V
authors.lastname: Lánská
authors.forename: J
authors.initials: J
authors.lastname: Rynekrová
authors.forename: L
authors.initials: L
authors.lastname: Zlatohlávek
authors.forename: M
authors.initials: M
authors.lastname: Prusíková
authors.forename: R
authors.initials: R
authors.lastname: Ceška
authors.forename: V
authors.initials: V
authors.lastname: Adámková
mesh_terms: D000368:Aged; D000483:Alleles; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000235:genetics; D000069059:Atorvastatin; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin