Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk

Aims: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. Patien...

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Published in:	Journal of medical genetics Vol. 43; no. 12; pp. 943 - 949
Main Authors:	Humphries, S E, Whittall, R A, Hubbart, C S, Maplebeck, S, Cooper, J A, Soutar, A K, Naoumova, R, Thompson, G R, Seed, M, Durrington, P N, Miller, J P, Betteridge, D J B, Neil, H A W
Format:	Journal Article
Language:	English
Published:	London BMJ Publishing Group Ltd 01-12-2006 BMJ BMJ Publishing Group LTD BMJ Group
Subjects:	Adult Apolipoproteins B - genetics Biological and medical sciences Cardiovascular disease CHD Cholesterol, HDL - blood Cholesterol, LDL - blood Coronary Disease - blood Coronary Disease - genetics coronary heart disease Disorders of blood lipids. Hyperlipoproteinemia DNA Mutational Analysis Female Fundamental and applied biological sciences. Psychology Gene Frequency Genes Genetics of eukaryotes. Biological and molecular evolution Health risk assessment Heart attacks Humans Hyperlipoproteinemia Type II - blood Hyperlipoproteinemia Type II - genetics LDL LDLR Letter to JMG Linkage Disequilibrium Lipids - blood low-density lipoprotein low-density lipoprotein receptor Male Medical genetics Medical sciences Metabolic diseases Middle Aged Molecular and cellular biology Mutation Mutation - genetics Odds Ratio PCR polymerase chain reaction Polymorphism, Single-Stranded Conformational Proprotein Convertase 9 Proprotein Convertases Receptors, LDL - genetics Risk Factors Serine Endopeptidases - genetics single-strand conformational polymorphism SSCP United Kingdom United Kingdom Europe United Kingdom > UK Human Metabolic diseases Cardiovascular disease Lipids Patient Risk Hyperlipoproteinemia Lipoprotein Coronary heart disease Cholesterol Genetic disease Blood plasma Hypercholesterolemia Risk factor Genetics Dyslipemia
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Summary:	Aims: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. Patients and methods: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6–10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. Results: Mutations were detected in 253 (61.9%) patients: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). Conclusions: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.
Bibliography:	ark:/67375/NVC-7GCZBDRG-1 local:0430943 PMID:17142622 Correspondence to:  S E Humphries  Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, The Rayne Building, Royal Free and University College London Medical School, London WC1E 6JJ, UK; rmhaseh@ucl.ac.uk href:jmedgenet-43-943.pdf istex:2C0C70644DB4B1BB870C7E34AE7B0047F1DBF38D ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 SourceType-Other Sources-1 ObjectType-Article-2 content type line 63 ObjectType-Correspondence-1
ISSN:	0022-2593 1468-6244 1468-6244
DOI:	10.1136/jmg.2006.038356