title: Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia.
abstract: Background Familial hypercholesterolemia is a common autosomal dominant disease, caused by mutations leading to elevated low-density lipoprotein (LDL) cholesterol and, if untreated, to premature cardiovascular disease. Methods Patients (young adults with a family history of hypercholesterolaemia or premature cardiovascular disease) with LDL cholesterol concentration ≥4.9 mmol/l, after excluding Familial Combined Hyperlipidaemia, were evaluated for causative mutations, Dutch Lipid Clinic Network score calculation and non-invasive ultrasound examination of carotid arteries. Results Of the 263 patients, 210 were heterozygotes for LDL receptor ( LDLR) mutations, four had APOB gene mutations, one PCSK9 gene mutation, while 48 had no evidence of mutations. Among 194 unrelated index cases 149 had mutations (77%). Among patients with LDLR mutations ( n = 145), there were five compound heterozygotes, 75 patients with null mutations and 65 with missense mutations. As many as 178 patients underwent a follow-up and treatment (statin ± ezetimibe), achieving a mean reduction of 49% in LDL cholesterol, with 21% of patients reaching the LDL goal of 2.6 mmol/l. In a multivariate analysis, carotid plaques, at ultrasound examination, were associated with the presence of genetic mutation ( p = 0.001), LDL cholesterol ( p < 0.001), Dutch Lipid Clinic Network score ( p < 0.001), independently of age, gender, smoking habits and systolic blood pressure. The presence of carotid plaque ( p = 0.017), LDL cholesterol ( p < 0.003), Dutch Lipid Clinic Network score ( p < 0.001) were independently associated with premature cardiovascular disease. Conclusions We identified patients with causative mutations in 82% of the cases under study. In addition to LDL cholesterol and Dutch Lipid Clinic Network score, carotid plaques in ultrasound evaluation provide direct evidence of premature vascular disease and are associated with high risk for cardiovascular events.
authors.affiliation: 1 Dipartimento di Medicina Clinica e Chirurgia, Università 'Federico II' di Napoli, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rubba
authors.affiliation: 1 Dipartimento di Medicina Clinica e Chirurgia, Università 'Federico II' di Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gentile
authors.affiliation: 1 Dipartimento di Medicina Clinica e Chirurgia, Università 'Federico II' di Napoli, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Marotta
authors.affiliation: 2 UO Medicina Interna, AORN 'A Cardarelli' di Napoli, Italy.
authors.forename: Arcangelo
authors.initials: A
authors.lastname: Iannuzzi
authors.affiliation: 1 Dipartimento di Medicina Clinica e Chirurgia, Università 'Federico II' di Napoli, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Sodano
authors.affiliation: 1 Dipartimento di Medicina Clinica e Chirurgia, Università 'Federico II' di Napoli, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: De Simone
authors.affiliation: 1 Dipartimento di Medicina Clinica e Chirurgia, Università 'Federico II' di Napoli, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Jossa
authors.affiliation: 1 Dipartimento di Medicina Clinica e Chirurgia, Università 'Federico II' di Napoli, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Iannuzzo
authors.affiliation: 3 CEINGE S.c.a r.l. Biotecnologie Avanzate, Napoli, Italy.|4 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Carola
authors.initials: C
authors.lastname: Giacobbe
authors.affiliation: 5 IRCCS Fondazione SDN, Napoli, Italy.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Di Taranto
authors.affiliation: 3 CEINGE S.c.a r.l. Biotecnologie Avanzate, Napoli, Italy.|4 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Fortunato
mesh_terms: D017668:Age of Onset; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D053299:Apolipoprotein B-100 / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control; D059168:Carotid Intima-Media Thickness; D008078:Cholesterol, LDL / Q000097:blood; D004252:DNA Mutational Analysis; D000069438:Ezetimibe / Q000627:therapeutic use; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D007558:Italy / Q000453:epidemiology; D009154:Mutation; D059645:Mutation Rate; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D015995:Prevalence; D000071449:Proprotein Convertase 9 / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: C569471:APOB protein, human; D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D000069438:Ezetimibe
keywords: Familial hypercholesterolaemia; carotid plaques; mutations; treatment