title: Pharmacogenetic aspects in familial hypercholesterolemia with the special focus on FHMarburg (FH p.W556R).
abstract: OBJECTIVE
  Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder caused by mutations in the low density lipoprotein receptor (LDLR) gene. FH is characterized by elevated plasma LDL cholesterol, premature atherosclerosis, and a high risk of premature myocardial infarction. In general, mutations within LDLR gene can cause five different classes of defects, namely: class I defect: no LDLR synthesis; class II defect: no LDLR transport; class III defect: no low density lipoprotein (LDL) to LDLR binding; class IV defect: no LDLR/LDL internalization; and class V defect: no LDLR recycling. One might expect that both the class of LDLR defect as well as the precise mutation influences the severity of hypercholesterolemia on one hand and the response on drug treatment on the other. To clarify this question we studied the effect of the LDLR mutation p.W556R in two heterozygote subjects.
  
  
  RESULTS
  We found that two heterozygote FH patients with the LDLR mutation p.W556R causing a class II LDLR defect (transport defective LDLR) respond exceedingly well to the treatment with simvastatin 40 mg/ezetimibe 10 mg. There was a LDL cholesterol decrease of 55 and 64%, respectively. In contrast, two affected homozygote p.W556R FH patients, in the mean time undergoing LDL apheresis, had no response to statin but a 15% LDL cholesterol decrease on ezetimibe monotherapy.
  
  
  CONCLUSIONS
  The LDLR mutation p.W556R is a frequent and severe class II defect for FH. The affected homozygote FH patients have a total loss of the functional LDLR and-as expected-do not respond on statin therapy and require LDL apheresis. In contrast, heterozygote FH patients with the same LDLR defect respond exceedingly well to standard lipid-lowering therapy, illustrating that the knowledge of the primary LDLR defect enables us to foresee the expected drug effects.
authors.affiliation: Department of Internal Medicine, Cardiology, Philipps-University, Baldingerstr.1, 35033 Marburg, Germany. juergen.schaefer@uni-marburg.de
authors.forename: Juergen R
authors.initials: JR
authors.lastname: Schaefer
authors.forename: Bilgen
authors.initials: B
authors.lastname: Kurt
authors.forename: Alexander
authors.initials: A
authors.lastname: Sattler
authors.forename: Günter
authors.initials: G
authors.lastname: Klaus
authors.forename: Muhidien
authors.initials: M
authors.lastname: Soufi
mesh_terms: D000328:Adult; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001384:Azetidines / Q000627:therapeutic use*; D001781:Blood Component Removal / Q000379:methods; D008078:Cholesterol, LDL / Q000097:blood; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D009154:Mutation; D010597:Pharmacogenetics; D011973:Receptors, LDL / Q000235:genetics*; D012720:Severity of Illness Index; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D019821:Simvastatin