Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.

Abstract

OBJECTIVE:

To determine the utility of secondary stratification measures to improve the ascertainment of index cases of familial hypercholesterolaemia (FH).

DESIGN:

A retrospective study of genotyped index patients with Simon Broome (SB) FH.

SETTING:

University teaching hospital.

PATIENTS:

204 patients aged 55±14 years; 36% had tendon xanthoma (TX), 21% had coronary heart disease (CHD), low-density lipoprotein cholesterol (LDL-C) was 6.20±2.24 mmol/l and 55% had genetic FH.

INTERVENTIONS:

The effects of different staging systems (SB vs Dutch criteria), presence of TX, use of LDL-C level, personal history of CHD and imaging evidence of atheroma by carotid intima-media thickness or coronary artery calcium score to identify genetic FH was explored.

OUTCOME MEASURES:

Changes in C-statistic and net reclassification index (NRI).

RESULTS:

SB criteria gave a C-statistic of 0.64 comprising C=0.65 in TX(+) and C=0.5 in TX(-) patients. Genetic FH was present in 75% of TX(+) compared with 44% in TX(-) patients. The Dutch criteria gave C=0.72. Addition of imaging criteria to prior CHD raised C=0.64 to C=0.65 in all patients with a NRI of 19% (p=0.06). In TX(-) patients imaging raised C=0.50 to C=0.65 with a NRI of 0.38 (p=0.001) and a weighted comparison index of 0.28, implying the detection of 14 more FH cases per thousand.

CONCLUSIONS:

Patients with tendon xanthoma (definite FH) should be genotyped. In patients with possible FH, the presence of a personal history of CHD or imaging evidence of increased atheroma offers the best method of identifying index patients likely to have monogenic FH.

• Authors: Rosemary E J Clarke, Soundrie T Padayachee, Rebecca Preston, Zofia McMahon, Mitchell Gordon, Colin Graham, Martin A Crook, Anthony S Wierzbicki
• Journal: Heart (British Cardiac Society) (Heart) Vol. 99 Issue 3 Pg. 175-80 (Feb 2013) ISSN: 1468-201X [Electronic] England
• PMID: 23213176 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Cholesterol, LDL

Topics

• Cholesterol, LDL (blood)
• Coronary Artery Disease (diagnosis, etiology, genetics)
• Diagnosis, Differential
• Diagnostic Imaging (methods, standards)
• Female
• Follow-Up Studies
• Genetic Testing (methods, standards)
• Humans
• Hyperlipoproteinemia Type II (complications, diagnosis, genetics)
• Male
• Middle Aged
• Phenotype
• Practice Guidelines as Topic
• Reproducibility of Results
• Retrospective Studies
• Risk Factors