A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

Author Acuna-Alonzo, Victor Google Scholar
Flores-Dorantes, Teresa Google Scholar
Kruit, Janine K. Google Scholar
Villarreal-Molina, Teresa Google Scholar
Arellano-Campos, Olimpia Google Scholar
Huenemeier, Tabita Google Scholar
Moreno-Estrada, Andres Google Scholar
Guadalupe Ortiz-Lopez, Ma Google Scholar
Villamil-Ramirez, Hugo Google Scholar
Leon-Mimila, Paola Google Scholar
Villalobos-Comparan, Marisela Google Scholar
Jacobo-Albavera, Leonor Google Scholar
Ramirez-Jimenez, Salvador Google Scholar
Sikora, Martin Google Scholar
Zhang, Lin-Hua Google Scholar
Pape, Terry D. Google Scholar
Angeles Granados-Silvestre, Ma de Google Scholar
Montufar-Robles, Isela Google Scholar
Tito-Alvarez, Ana M. Google Scholar
Zurita-Salinas, Camilo Google Scholar
Bustos-Arriaga, Jose Google Scholar
Cedillo-Barron, Leticia Google Scholar
Gomez-Trejo, Celta Google Scholar
Barquera-Lozano, Rodrigo Google Scholar
Vieira Filho, Joao Paulo Botelho Autor UNIFESP Google Scholar
Granados, Julio Google Scholar
Romero-Hidalgo, Sandra Google Scholar
Huertas-Vazquez, Adriana Google Scholar
Gonzalez-Martin, Antonio Google Scholar
Gorostiza, Amaya Google Scholar
Bonatto, Sandro L. Google Scholar
Rodriguez-Cruz, Maricela Google Scholar
Wang, Li Google Scholar
Tusie-Luna, Teresa Google Scholar
Aguilar-Salinas, Carlos A. Google Scholar
Lisker, Ruben Google Scholar
Moises, Regina S. Autor UNIFESP Google Scholar
Menjivar, Marta Google Scholar
Salzano, Francisco M. Google Scholar
Knowler, William C. Google Scholar
Catira Bortolini, M. Google Scholar
Hayden, Michael R. Google Scholar
Baier, Leslie J. Google Scholar
Canizales-Quinteros, Samuel Google Scholar
Institution Univ Nacl Autonoma Mexico
Univ British Columbia
Univ Fed Rio Grande do Sul
Stanford Univ
Hosp Juarez Mexico
Labs Zurita & Zurita
Universidade Federal de São Paulo (UNIFESP)
Inst Nacl Med Genom
Cedars Sinai Med Ctr
Univ Complutense Madrid
Pontificia Univ Catolica Rio Grande do Sul
Mexican Inst Social Secur
Chinese Acad Sci
Abstract It 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 x 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.
Language English
Sponsor Consejo Nacional de Ciencia y Tecnologia (CONACYT) Mexico
Fundacion Mexicana para la Salud-Silanes
National Institute of Digestive and Kidney Diseases (NIDDK), NIH
Canadian Institutes of Health Research (CIHR)
Michael Smith Foundation for Health Research (MSFHR)
Grant number Consejo Nacional de Ciencia y Tecnologia (CONACYT) Mexico: 69856
Fundacion Mexicana para la Salud-Silanes: 660
Date 2010-07-15
Published in Human Molecular Genetics. Oxford: Oxford Univ Press, v. 19, n. 14, p. 2877-2885, 2010.
ISSN 0964-6906 (Sherpa/Romeo, impact factor)
Publisher Oxford Univ Press
Extent 2877-2885
Origin http://dx.doi.org/10.1093/hmg/ddq173
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000279469100012
URI http://repositorio.unifesp.br/handle/11600/32725

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