Lipid phenotype and heritage pattern in families with genetic hypercholesterolemia not related to LDLR, APOB, PCSK9, or APOE

Jarauta, E. ; Pérez-Ruiz, M. R. ; Pérez-Calahorra, S. (Universidad de Zaragoza) ; Mateo-Gallego, R. ; Cenarro, A. ; Cofán, M. ; Ros, E. ; Civeira, F. (Universidad de Zaragoza) ; Tejedor, M. T. (Universidad de Zaragoza)

Resumen: Background: A substantial proportion of individuals clinically diagnosed as familial hypercholesterolemia (FH) do not carry pathogenic mutations in candidate genes. Whether in them the high cholesterol trait is transmitted monogenically has not been studied. Objectives: We assessed the inheritance pattern, penetrance, and expression of high low-density lipoprotein (LDL)-cholesterol (LDLc) in families with genetic hypercholesterolemia (GH) without known causative mutations (non-FH-GH). Methods: The study included probands with a clinical diagnosis of FH and their families attending 2 lipid clinics in Spain. Inclusion criteria for probands were LDLc >95th percentile, triglycerides 90th percentile, >5 points in the Dutch Lipid Clinic Network criteria score, and absence of mutations in LDLR, APOB, PCSK9 or APOE. Eleven FH families with a LDLR mutation were also examined for comparison. Results: We analyzed 49 non-FH-GH probands and 277 first-and second-degree relatives. LDLc was >90th percentile in 37.8% of blood relatives, at concentrations similar to those of probands. LDLc had a normal distribution in non-FH-GH families, in contrast with a bimodal distribution in FH families. When a dominant model was tested, family-based association tests gave much lower heritability values for total cholesterol and LDLc in non-FH-GH (0.39 and 0.32, respectively) than in FH (0.78 and 0.61, respectively). Conclusions: Non-FH-GH families have a milder lipid phenotype than genetically defined FH. The heritage pattern of LDLc in non-FH-GH does not fit with a monogenic disorder. Our findings support the concept that most non-FH-GHs are polygenic hypercholesterolemias.

Idioma: Inglés

DOI: 10.1016/j.jacl.2016.09.011

Año: 2016

Publicado en: Journal of Clinical Lipidology 10, 6 (2016), 1397-1405.e2
ISSN: 1933-2874

Factor impacto JCR: 5.812 (2016)

Categ. JCR: PHARMACOLOGY & PHARMACY rank: 17 / 256 = 0.066 (2016) - Q1 - T1

Factor impacto SCIMAGO: 2.177 - Cardiology and Cardiovascular Medicine (Q1) - Nutrition and Dietetics (Q1) - Internal Medicine (Q1) - Endocrinology, Diabetes and Metabolism (Q1)

Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0055
Financiación: info:eu-repo/grantAgreement/ES/MINECO/PI12-01087
Financiación: info:eu-repo/grantAgreement/ES/MINECO/PI12-01321
Financiación: info:eu-repo/grantAgreement/ES/MINECO/PI12-01703

Tipo y forma: Article (PostPrint)

Área (Departamento): Área Genética (Dpto. Anatom.,Embri.Genét.Ani.)
Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)