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Title: A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans
Authors: Acuna-Alonzo, Victor
Flores-Dorantes, Teresa
Kruit, Janine K.
Villarreal-Molina, Teresa
Arellano-Campos, Olimpia
Huenemeier, Tabita
Moreno-Estrada, Andres
Guadalupe Ortiz-Lopez, Ma
Villamil-Ramirez, Hugo
Leon-Mimila, Paola
Villalobos-Comparan, Marisela
Jacobo-Albavera, Leonor
Ramirez-Jimenez, Salvador
Sikora, Martin
Zhang, Lin-Hua
Pape, Terry D.
Angeles Granados-Silvestre, Ma de
Montufar-Robles, Isela
Tito-Alvarez, Ana M.
Zurita-Salinas, Camilo
Bustos-Arriaga, Jose
Cedillo-Barron, Leticia
Gomez-Trejo, Celta
Barquera-Lozano, Rodrigo
Vieira Filho, Joao Paulo Botelho [UNIFESP]
Granados, Julio
Romero-Hidalgo, Sandra
Huertas-Vazquez, Adriana
Gonzalez-Martin, Antonio
Gorostiza, Amaya
Bonatto, Sandro L.
Rodriguez-Cruz, Maricela
Wang, Li
Tusie-Luna, Teresa
Aguilar-Salinas, Carlos A.
Lisker, Ruben
Moises, Regina S. [UNIFESP]
Menjivar, Marta
Salzano, Francisco M.
Knowler, William C.
Catira Bortolini, M.
Hayden, Michael R.
Baier, Leslie J.
Canizales-Quinteros, Samuel
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
Issue Date: 15-Jul-2010
Publisher: Oxford Univ Press
Citation: Human Molecular Genetics. Oxford: Oxford Univ Press, v. 19, n. 14, p. 2877-2885, 2010.
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.
ISSN: 0964-6906
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