Produção Nacional
Revisado por pares
A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans
2010; Oxford University Press; Volume: 19; Issue: 14 Linguagem: Inglês
10.1093/hmg/ddq173
ISSN1460-2083
AutoresVíctor Acuña-Alonzo, María Teresa Flores-Dorantes, Janine K. Kruit, Teresa Villarreal‐Molina, Olimpia Arellano‐Campos, Tábita Hünemeier, Andrés Moreno‐Estrada, María Guadalupe Ortiz‐López, Hugo Villamil‐Ramírez, Paola León‐Mimila, Marisela Villalobos‐Comparán, Leonor Jacobo‐Albavera, Salvador Ramı́rez-Jiménez, Martin Sikora, Linhua Zhang, Terry D. Pape, Ma de Ángeles Granados-Silvestre, Isela Montúfar‐Robles, Ana M. Tito-Álvarez, Camilo Zurita-Salinas, José Bustos‐Arriaga, Leticia Cedillo‐Barrón, Celta Gómez-Trejo, Rodrigo Barquera, João Paulo Botelho Vieira‐Filho, Julio Granados, Sandra Romero‐Hidalgo, Adriana Huertas‐Vázquez, Antonio González‐Martín, Amaya Gorostiza, Sandro L. Bonatto, Maricela Rodríguez‐Cruz, Li Wang, Teresa Tusié‐Luna, Carlos A. Aguilar‐Salinas, R Lisker, Regina S. Moisés, Marta Menjívar, Francisco M. Salzano, William C. Knowler, María Cátira Bortolini, Michael R. Hayden, Leslie J. Baier, Samuel Canizales‐Quinteros,
Tópico(s)Drug Transport and Resistance Mechanisms
ResumoIt has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 × 10−11) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.
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