J Med Genet

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J Med Genet. Published Online First: 26 June 2006. doi:10.1136/jmg.2005.038356
Copyright © 2006 by the BMJ Publishing Group Ltd.
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Letters to JMG

Genetic causes of Familial Hypercholesterolaemia in UK patients: relation to plasma lipid levels and coronary heart disease risk

Steve E. Humphries 1*, Roslyn A. Whittall 1, Christina S. Hubbart 1, Sarah Maplebeck 1, Jacqueline A. Cooper 1, Anne Soutar 2, Rossi Naoumova 2, Gilbert R. Thompson 2, Mary Seed 3, Paul N. Durrington 4, J. Paul Miller 5, D. John B. Betteridge 6 and H. A. W. Neil 7

1 University College London, United Kingdom
2 Hammersmith Hospital, United Kingdom
3 Charing Cross Hospital
4 University of Manchester
5 Withington Hospital
6 University College London
7 The Radcliffe Infirmary

* To whom correspondence should be addressed. E-mail: rmhaseh{at}ucl.ac.uk.

Accepted 10 June 2006


*   Abstract

Aims: In UK patients with clinically-defined definite familial hypercholesterolaemia (FH) to determine the relative frequency of mutations in three different genes (LDLR, APOB, PCSK9), and to examine their impact in development of coronary heart disease (CHD).

Subject and Methods: 409 FH patients (158 with CHD) were studied. The LDLR was partially screened by SSCP (exons 3, 4, 6-10 and 14) and using a commercial kit for gross deletions/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%) in 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 1.10-3.06), for APOB 3.40 (0.71-16.36), and for PCSK9 19.96 (1.88-211.5), (p=0.0003 overall). The high risk in LDLR and PCSK9 p.Y374-carrying subjects was partly explained by their higher pre-treatment cholesterol levels (LDLR, PCSK9, no-mutation, 10.29±1.85mmol/l, 13.12±1.69mmol/l, 9.85±1.90mmol/l, p=0.0002). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than subjects with no identified mutation (LDL-C, 6.77±1.82mmol/l versus 4.19±1.26mmol/l, p=0.0001, HDL-C 1.09±0.27mmol/l versus 1.36±0.36mmol/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 FH patients. Mutations in PCSK9 appear uncommon in UK FH patients.

Keywords: Familial defective APOB, PCSK9, Low density lipoprotein receptor






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