Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery disease in patients with severe hypercholesterolaemia.
OBJECTIVE
The impact of positive clinical signs (xanthoma and/or family history) and positive familial hypercholesterolaemia (FH) mutation status on risk of coronary artery disease (CAD) over and above that predicted by low-density lipoprotein (LDL) cholesterol level alone has not been fully determined. We assessed whether positive clinical signs and genetic FH diagnosis affected CAD risk among subjects with significantly elevated LDL cholesterol levels (≥180 mg/dL, or ≥140 mg/dL in subjects <15 years of age).


RESULTS
Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 636 patients with severe hypercholesterolaemia (mean age, 45 years; 300 males [47%], CAD diagnosis, 185 [29%]), and the presence of clinical FH signs (xanthoma and/or family history) were assessed. CAD prevalence was compared between four subject groups categorized based on these parameters. Compared with the reference group without FH mutations or clinical signs of FH, subjects with clinical signs of FH or FH mutations had three- to four-fold higher odds of developing CAD (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.5-14.5; P = 0.0011 and OR, 3.4; 95% CI, 1.0-10.9; P = 0.0047, respectively), whereas those with clinical signs of FH and FH mutation(s) had >11-fold higher odds of developing CAD (OR, 11.6; 95% CI, 4.4-30.2; P = 1.1 × 10-5) after adjusting for known risk factors including LDL cholesterol.


CONCLUSIONS
Our findings revealed an additive effect of positive clinical signs of FH and positive FH mutation status to CAD risk among patients with significantly elevated LDL cholesterol.
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Hayato
H
Tada
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Masa-Aki
MA
Kawashiri
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Atsushi
A
Nohara
Department of Laboratory Science, Molecular Biochemistry and Molecular Biology, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan.
Akihiro
A
Inazu
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Hiroshi
H
Mabuchi
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Masakazu
M
Yamagishi
D000328:Adult; D017677:Age Distribution; D053299:Apolipoprotein B-100 / Q000235:genetics; D008078:Cholesterol, LDL / Q000235:genetics / Q000378:metabolism; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000071449:Proprotein Convertase 9 / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods
C569471:APOB protein, human; D053299:Apolipoprotein B-100; D008078:Cholesterol, LDL; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
Familial hypercholesterolaemia; Genetics; Low-density lipoprotein receptor; Proprotein convertase subtilisin/kexin type 9