Published online before print October 13, 2005, doi: 10.1161/01.ATV.0000190668.94752.ab
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Severe Hypercholesterolemia in Four British Families With the D374Y Mutation in the PCSK9 Gene
Long-Term Follow-Up and Treatment Response
From the MRC Clinical Sciences Centre (R.P.N., I.T., D.P., C.N., S.D.H., A.K.S.), Hammersmith Hospital, London, UK; University of Cape Town (A.D.M.), Republic of South Africa; and University Hospital (C.v.H.), Aintree, Liverpool, UK.
Correspondence to Dr Rossi Naoumova, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Rd, London W12 0NN, UK. E-mail rossi.naoumova{at}csc.mrc.ac.uk
Objective— Analysis of long-term (30 years) clinical history and response to treatment of 13 patients with the D374Y mutation of PCSK9 (PCSK9 patients) from 4 unrelated white British families compared with 36 white British patients with heterozygous familial hypercholesterolemia attributable to 3 specific mutations in the low-density lipoprotein (LDL) receptor gene (LDLR) known to cause severe phenotype.
Methods and Results— The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8±14.7 versus 30.2±15.7 years; P=0.003), had higher pretreatment serum cholesterol levels (13.6±2.9 versus 9.6±1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1±3.0 versus 6.5±0.9 mmol/L; P=0.006), atorvastatin (9.6±2.9 versus 6.4±1.0 mmol/L; P=0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0±1.6 versus 5.4±1.0 mmol/L; P=0.001), and were affected >10 years earlier by premature coronary artery disease (35.2±4.8 versus 46.8±8.9 years; P=0.002). LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients.
Conclusions— These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications.
Thirteen British patients with the D374Y mutation of PCSK9 were compared with 36 similar patients with heterozygous familial hypercholesterolemia caused by LDLR mutations and were found to have higher total cholesterol levels, pretreatment and on-treatment with statins, and were affected >10 years earlier by severe atherosclerosis.
Key Words: coronary disease • atherosclerosis • familial hypercholesterolemia • statins • ezetimibe
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