Virginia G Bañares1, Pablo Corral2, Ana Margarida Medeiros3, María Beatriz Araujo4, Alfredo Lozada5, Juan Bustamante6, Roxana Cerretini7, Graciela López8, Mafalda Bourbon3, Laura E Schreier8. 1. Departamento de Genética Experimental, Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud -ANLIS, "Dr Carlos Malbrán", Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: vgbaniares@hotmail.com. 2. Departamento Investigación, Facultad de Medicina, Universidad FASTA, Buenos Aires, Argentina. 3. Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis, Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal; Faculty of Sciences, University of Lisbon, BioISI - Biosystems & Integrative Sciences Institute, Lisboa, Portugal. 4. Servicio de Nutrición, Hospital Nacional de Pediatría "Dr Juan P. Garraham", Ciudad Autónoma de Buenos Aires, Argentina. 5. Clínica de Lípidos, Universidad Austral, Buenos Aires, Argentina. 6. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina; Facultad de Ingeniería, Universidad Nacional de Entre Ríos, Entre Ríos, Argentina. 7. Departamento de Genética Experimental, Centro Nacional de Genética Médica, Administración Nacional de Laboratorios e Institutos de Salud -ANLIS, "Dr Carlos Malbrán", Ciudad Autónoma de Buenos Aires, Argentina. 8. Laboratorio de Lípidos y Aterosclerosis, Facultad de Farmacia y Bioquímica, Departamento de Bioquímica Clínica, Universidad de Buenos Aires, Buenos Aires, Argentina; Universidad de Buenos Aires, Instituto de Fisiopatologia y Bioquímica Clinica, INFIBIOC, Buenos Aires, Argentina.
Abstract
BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. OBJECTIVE: The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. METHODS: Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. RESULTS: Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics' analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. CONCLUSION: This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina.
BACKGROUND:Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol and early cardiovascular disease. As cardiovascular disease is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. OBJECTIVE: The aim of our study was to identify families with FH and to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. METHODS: Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, multiplex ligation-dependent probe amplification, and bioinformatics tools. RESULTS: Twenty genetic variants were identified among 24 cases (73%), 95% on the low-density lipoprotein receptor gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A, c.170A>C p.(Asp57Ala), c.684G>C p.(Glu228Asp), and c.1895A>T p.(Asn632Ile); the bioinformatics' analysis revealed clear destabilizing effects for 2 of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than 1 case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, 3 compound heterozygotes, and 1 double heterozygote were identified. CONCLUSION: This study characterizes for the first time in Argentina genetic variants associated with FH and suggest that the allelic heterogeneity of the FH in the country could have 1 relative common low-density lipoprotein receptor mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol-lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina.