Diagnostic yield of sequencing familial hypercholesterolemia genes in individuals with primary hypercholesterolemia
Rev Esp Cardiol (Engl Ed). 2021 Aug;74(8):664-673.
doi: 10.1016/j.rec.2020.06.003.
Epub 2020 Jul 11.
[Article in
English,
Spanish]
Affiliations
- 1 Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Zaragoza, Spain.
- 2 Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Zaragoza, Spain; Departamento de Medicina, Psiquiatría y Dermatología, Universidad de Zaragoza, Zaragoza, Spain. Electronic address: civeira@unizar.es.
- 3 Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Zaragoza, Spain; Departamento de Fisiatría y Enfermería, Universidad de Zaragoza, Zaragoza, Spain.
- 4 Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Zaragoza, Spain; Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID), Zaragoza, Spain.
- 5 Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, Zaragoza, Spain; Unidad de Prevención Cardiovascular, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
- 6 Departamento de Anatomía, Embriología y Genética, Universidad de Zaragoza, Zaragoza, Spain.
- 7 Departamento de I+D, Progenika Biopharma, a Grifols Company, Derio, Vizcaya, Spain.
- 8 Instituto Biofisika (UPV/EHU, CSIC), Leioa, Vizcaya, Spain.
- 9 Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Zaragoza, Spain; Departamento de Bioquímica y Biología Molecular, Universidad del País Vasco, UPV/EHU, Bilbao, Spain; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain.
Abstract
Introduction and objectives:
Our objective was to approximate the prevalence of mutations in candidate genes for familial hypercholesterolemia (FH) in a middle-aged Spanish population and to establish the predictive value of criteria for clinical suspicion in the detection of causative mutations.
Methods:
Unrelated individuals aged ≥ 18 years from the Aragon Workers' Health Study (AWHS) with high low-density lipoprotein cholesterol (LDL-C) and clinical suspicion of FH (participants with LDL-C concentrations above the 95th percentile, participants with premature cardiovascular disease and/or participants with high LDL-C [130 mg/dL] under statin therapy), assuming that any participant with FH exhibits at leats 1 trait, were selected and the LDLR, APOB, PCSK9, APOE, STAP1 and LDLRAP1 genes were sequenced by next generation sequencing technology.
Results:
Of 5400 individuals from the AWHS, 4514 had complete data on lipid levels and lipid-lowering drugs, 255 participants (5.65%) met the criteria for suspicion of FH, 24 of them (9.41%) were diagnosed with hyperlipoproteinemia(a), and 16 (6.27% of those sequenced) were found to carry causative mutations in candidate genes: 12 participants carried 11 different pathogenic LDLR alleles and 4 participants carried 1 pathogenic mutation in PCSK9. LDL-C concentrations> 220 mg/dL and LDL-C> 130 mg/dL despite statin therapy showed the strongest association with the presence of mutations (P=.011).
Conclusions:
Our results show that the prevalence of FH in Spain is 1:282 and suggest that the combination of high untreated LDL-C and high levels of LDL-C despite statin therapy are the best predictors of a positive FH genetic test.
Keywords:
Criterios de sospecha de HF; FH prevalence; FH suspicion criteria; LDLR; Lipoprotein(a); Lipoproteína (a); Mutación en genes candidatos; Mutation in candidate genes; PCSK9; Prevalencia HF; STAP1.
Copyright © 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.
MeSH terms
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Humans
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Hypercholesterolemia* / diagnosis
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Hypercholesterolemia* / epidemiology
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Hypercholesterolemia* / genetics
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Hyperlipoproteinemia Type II* / diagnosis
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Hyperlipoproteinemia Type II* / epidemiology
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Hyperlipoproteinemia Type II* / genetics
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Middle Aged
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Mutation
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Proprotein Convertase 9 / genetics
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Spain / epidemiology
Substances
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PCSK9 protein, human
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Proprotein Convertase 9