Polygenic markers in patients diagnosed of autosomal dominant hypercholesterolemia in Catalonia : distribution of weighted LDL-c-raising SNP scores and refinement of variant selection
Martín-Campos, Jesús Maria (Institut d'Investigació Biomèdica Sant Pau)
Ruiz-Nogales, Sheila (Institut d'Investigació Biomèdica Sant Pau)
Ibarretxe, Daiana (Hospital Universitari Joan XXIII de Tarragona. Institut d'Investigació Sanitària Pere Virgili)
Ortega, Emilio (Hospital Clínic. Servei d'Endocrinologia i Nutrició)
Sánchez-Pujol, Elisabet (Hospital General de Granollers)
Royuela-Juncadella, Meritxell (Altahia. Xarxa Assistencial Universitària de Manresa. Servei de Medicina Interna)
Vila, Àlex (Hospital de Figueres)
Guerrero, Carolina (Consorci Sanitari Hospital de Terrassa)
Zamora, Alberto (Hospital de Blanes. Corporació de Salut del Maresme i La Selva. Servei de Medicina Interna)
Soler i Ferrer, Cristina (Hospital de Santa Caterina (Salt, Girona))
Arroyo, Juan Antonio (Institut d'Investigació Biomèdica Sant Pau)
Carreras, Gemma (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i Medicina Preventiva i Salut Pública)
Martínez-Figueroa, Susana (Institut d'Investigació Biomèdica Sant Pau)
Roig, Rosa (Institut d'Investigació Biomèdica Sant Pau)
Plana, Núria (Hospital Universitari Joan XXIII de Tarragona. Institut d'Investigació Sanitària Pere Virgili)
Blanco Vaca, Francisco (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2020
Abstract:	Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30-70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46. 4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66. 4% of the patients if those with polygenic FH are added to the 37. 3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity.
Grants:	Ministerio de Economía y Competitividad PI14/01648 Instituto de Salud Carlos III PI18/00164
Note:	Altres ajuts: Fundació la Marató de TV3 grant 20152431
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Familial hypercholesterolemia ; Atherosclerosis ; Genetic risk scores ; Cardiovascular risk ; Molecular diagnosis
Published in:	Biomedicines, Vol. 8, Issue 9 (September 2020) , art. 353, ISSN 2227-9059

DOI: 10.3390/biomedicines8090353
PMID: 32942679

14 p, 1.1 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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