Pharmacogenetic aspects in familial hypercholesterolemia with the special focus on FHMarburg (FH p.W556R)
Tóm tắt
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. 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. 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.
Tài liệu tham khảo
Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47
Cummings RD, Kornfeld S, Schneider WJ, Hobgood KK, Tolleshaug H, Brown MS, Goldstein JL (1983) Biosynthesis of N- and O-linked oligosaccharides of the low density lipoprotein receptor. J Biol Chem 258:15261–15273
Davis CG, Van Driel IR, Russell DW, Brown MS, Goldstein JL (1987) The low density lipoprotein receptor. Identification of amino acids in cytoplasmic domain required for rapid endocytosis. J Biol Chem 262:4075–4082
Hobbs HH, Russell DW, Brown MS, Goldstein JL (1990) The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24:133–170
Austin MA, Hutter CM, Zimmern RL, Humphries SE (2004) Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol 160:421–429
Goldstein JL, Brown MS (1989) Familial Hypercholesterolemiahypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, (eds) The metabolic basis of inherited disease. McGraw-Hill, New York pp 1215–1250
Rader DJ, Cohen J, Hobbs HH (2003) Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 111:1795–1803
Sudhof TC, Goldstein JL, Brown MS, Russell DW (1985) The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228:815–822
Villeger L, Abifadel M, Allard D, Rabes JP, Thiart R, Kotze MJ et al (2002) The UMD-LDLR database: additions to the software and 490 new entries to the database. Hum Mutat 20:81–87
Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE (2008) Update and analysis of the university college london low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 72:485–498
Varret M, Abifadel M, Rabès JP, Boileau C (2008) Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet 73(1):1–13
Hobbs HH, Brown MS, Goldstein JL (1992) Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1:445–466
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low density lipoprotein cholesterol without use of the preparative ultracentrifuge. Clin Chem 18:499–502
Hackler R, Schaefer JR, Motzny S, Brand S, Kleine TO, Kaffarnik H, Steinmetz A (1994) Rapid determination of apolipoprotein E phenotypes from whole plasma by automated isoelectric focusing using PhastSystem and immunofixation. J Lipid Res 35:153–158
Nissen H, Guldberg P, Hansen AB, Petersen NE, Horder M (1996) Clinically applicable mutation screening in familial hypercholesterolemia. Hum Mutat 8:168–177
Soufi M, Sattler AM, Maerz W, Starke A, Herzum M, Maisch B, Schaefer JR (2004) A new but frequent mutation of apoB-100-apoB His3543Tyr. Atherosclerosis 174:11–16
Zschocke J, Schaefer JR (2003) Homozygous familial hypercholesterolaemia in identical twins. Lancet 361(9369):1641
Soufi M, Zschocke J, Quak E, Hofmann G, Maisch B, Schaefer JR (1999) First description of homozygous familial hypercholesterolemia (FH) in twins. Atherosclerosis Suppl. 2(147):34
Sozen MM, Whittall R, Oner C, Tokatli A, Kalkanoglu HS, Dursun A et al (2005) The molecular basis of familial hypercholesterolaemia in Turkish patients. Atherosclerosis 180:63–71
Soufi M, Kurt B, Schweer H, Sattler AM, Klaus G, Zschocke J, Schaefer JR (2009) Genetics and kinetics of familial hypercholesterolemia, with the special focus on FH-(Marburg) p.W556R. Atheroscler Suppl 10(5):5–11
Schmidt HH, Tietge UJ, Buettner J, Barg-Hock H, Offner G, Schweitzer S et al (2008) Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation. Clin Transplant 22:180–184
Abramson BL, Benlian P, Hanson ME, Lin J, Shah A, Tershakovec AM (2011) Response by sex to statin plus ezetimibe or statin monotherapy: a pooled analysis of 22,231 hyperlipidemic patients. Lipids Health Dis 10:146
Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB (2004) Ezetimibe Study Group. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 79(5):620–629
Heath KE, Gudnason V, Humphries SE, Seed M (1999) The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia. Atherosclerosis 143(1):41–54
Miltiadous G, Xenophontos S, Bairaktari E, Ganotakis M, Cariolou M, Elisaf M (2005) Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia. Pharmacogenet Genomics 15(4):219–225
Graham CA, McClean E, Ward AJ, Beattie ED, Martin S, O’Kane M et al (1999) Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia. Atherosclerosis 147:309–316
Vergopoulos A, Knoblauch H, Schuster H (2002) DNA testing for familial hypercholesterolemia: improving disease recognition and patient care. Am J Pharmacogenomics 2(4):253–262
Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F et al (2009) The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. J Pediatr 155:199–204
Ned Renée M, Sijbrands Eric JG (2011) Cascade screening for familial hypercholesterolemia (FH) (Internet). Version 11. PLoS currents: evidence on genomic tests. 2011: PMC3102597
Setia N, Verma IC, Khan B, Arora A (2012) Premature coronary artery disease and familial hypercholesterolemia: need for early diagnosis and cascade screening in the Indian population. Cardiol Res Pract 2012:658526. (Epub 27 Oct 2011)