- •Putative pathogenic mutations of 3 FH genes were in 32% of suspected FH patients.
- •The specificities of conventional diagnostic criteria were low in Korean FHs.
- •The best LDL-C threshold for mutations was 225 mg/dL.
- •LDL-C predicted mutations, while hypertension and low HDL-C predicted CAD.
Abstract
Background
Proper screening and diagnosis of familial hypercholesterolemia (FH) is of critical
importance for cardiovascular prevention. However, the clinical diagnosis of FH remains
difficult partly because its phenotype can vary between different ethnicities. The
aim of this study was to determine the clinical features and the best diagnostic approach
in Korean FH patients. The predictors of putative pathogenic mutations and coronary
artery disease (CAD) were also identified.
Methods and Results
Ninety-seven patients with low-density lipoprotein-cholesterol >190 mg/dL and xanthoma
or FH-compatible family history were included. Putative pathogenic mutations in LDLR, APOB, or PCSK9 genes were identified in 32% of the enrolled patients. The subjects were classified
according to four sets of clinical criteria (Simon Broome, Dutch, MEDPED, Japanese).
The mutation rates in definite type FH of Simon Broome or Dutch criteria were 35%–37%
and lower in our patients than in those of other countries. The mutation detection
rate by MEDPED criteria was 67%–75% and higher than those based on other criteria.
The best low-density lipoprotein-cholesterol (LDL-C) threshold for predicting mutations
was 225 mg/dL. LDL-C was found to be the only independent predictor of mutation carriers,
while hypertension and low high-density lipoprotein-cholesterol were predictive of
CAD.
Conclusions
The conventional clinical criteria showed limited mutation detection power and low
specificities in Korean FH patients, in whom the best LDL-C threshold for putative
mutation was 225 mg/dL. Traditional cardiovascular risk factors were also significantly
associated with CAD risk in this population.
Keywords
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References
- Use of targeted exome sequencing as a diagnostic tool for familial hypercholesterolaemia.J. Med. Genet. 2012; 49: 644-649
- Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.Am. J. Epidemiol. 2004; 160: 407-420
- Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.Lancet. 2013; 381: 1293-1301
- Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease : consensus statement of the European Atherosclerosis Society.Eur. Heart J. 2013; 34: 3478-3490
- Diagnosis and treatment of familial hypercholesterolaemia.Eur. Heart J. 2013; 34: 962-971
- Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation.J. Clin. Lipidol. 2014; 8: 148-172
- Coronary artery disease in heterozygous familial hypercholesterolemia patients with the same LDL receptor gene mutation.Circulation. 1995; 92: 290-295
- Accelerated subclinical coronary atherosclerosis in patients with familial hypercholesterolemia.Atherosclerosis. 2011; 219: 721-727
- Defining patients at extremely high risk for coronary artery disease in heterozygous familial hypercholesterolemia.J. Atheroscler. Thromb. 2012; 19: 369-375
- Three novel small deletion mutations of the LDL receptor gene in Korean patients with familial hypercholesterolemia.Clin. Genet. 1999; 55: 325-331
- Novel and recurrent mutations of the LDL receptor gene in Korean patients with familial hypercholesterolemia.Mol. Cells. 2004; 18: 63-70
- Identification of four novel mutations of the low-density lipoprotein receptor gene in Korean patients with familial hypercholesterolemia.Clin. Genet. 2000; 57: 225-229
- A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia.Atherosclerosis. 2003; 168: 1-14
- Multicenter study to determine the diagnosis criteria of heterozygous familial hypercholesterolemia in Japan.J. Atheroscler. Thromb. 2012; 19: 1019-1026
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet. Med. 2015; 17: 405-423
- The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.Atherosclerosis. 2005; 180: 155-160
- Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.Clin. Genet. 2010; 77: 572-580
- Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia.Am. J. Cardiol. 2010; 105: 1752-1758
- Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia.Am. J. Cardiol. 2008; 102: 1187-1193.e1
- Effectiveness of alternative strategies to define index case phenotypes to aid genetic diagnosis of familial hypercholesterolaemia.Heart. 2013; 99: 175-180
- Heterozygous familial hypercholesterolemia in Hong Kong Chinese. Study of 252 cases.Int. J. Cardiol. 2013; 167: 762-767
- Clinical features of familial hypercholesterolemia in Japan in a database from 1996−1998 by the Research Committee of the Ministry of Health, Labour and Welfare of Japan.J. Atheroscler. Thromb. 2004; 11: 146-151
- Evaluation of subclinical atherosclerosis by computed tomography coronary angiography and its association with risk factors in familial hypercholesterolemia.Atherosclerosis. 2010; 213: 486-491
- Difference in the risk factors for coronary, renal and other peripheral arteriosclerosis in heterozygous familial hypercholesterolemia.Circ. J. 2004; 68: 623-627
Article info
Publication history
Published online: August 28, 2015
Accepted:
August 24,
2015
Received in revised form:
August 2,
2015
Received:
April 27,
2015
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
