title: Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.
abstract: OBJECTIVE
  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.
  
  
  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%)
  
  
  METHODS
  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.
authors.forename: S E
authors.initials: SE
authors.lastname: Humphries
authors.forename: R A
authors.initials: RA
authors.lastname: Whittall
authors.forename: C S
authors.initials: CS
authors.lastname: Hubbart
authors.forename: S
authors.initials: S
authors.lastname: Maplebeck
authors.forename: J A
authors.initials: JA
authors.lastname: Cooper
authors.forename: A K
authors.initials: AK
authors.lastname: Soutar
authors.forename: R
authors.initials: R
authors.lastname: Naoumova
authors.forename: G R
authors.initials: GR
authors.lastname: Thompson
authors.forename: M
authors.initials: M
authors.lastname: Seed
authors.forename: P N
authors.initials: PN
authors.lastname: Durrington
authors.forename: J P
authors.initials: JP
authors.lastname: Miller
authors.forename: D J B
authors.initials: DJ
authors.lastname: Betteridge
authors.forename: H A W
authors.initials: HA
authors.lastname: Neil
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000235:genetics*; D015810:Linkage Disequilibrium; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D016017:Odds Ratio; D018807:Polymorphism, Single-Stranded Conformational; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000235:genetics; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics; D006113:United Kingdom
chemical_list: D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008055:Lipids; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases