title: A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.
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.
authors.affiliation: Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Universidad Nacional Autónoma de México, Mexico City 14000, Mexico.
authors.forename: Víctor
authors.initials: V
authors.lastname: Acuña-Alonzo
authors.forename: Teresa
authors.initials: T
authors.lastname: Flores-Dorantes
authors.forename: Janine K
authors.initials: JK
authors.lastname: Kruit
authors.forename: Teresa
authors.initials: T
authors.lastname: Villarreal-Molina
authors.forename: Olimpia
authors.initials: O
authors.lastname: Arellano-Campos
authors.forename: Tábita
authors.initials: T
authors.lastname: Hünemeier
authors.forename: Andrés
authors.initials: A
authors.lastname: Moreno-Estrada
authors.forename: Ma Guadalupe
authors.initials: MG
authors.lastname: Ortiz-López
authors.forename: Hugo
authors.initials: H
authors.lastname: Villamil-Ramírez
authors.forename: Paola
authors.initials: P
authors.lastname: León-Mimila
authors.forename: Marisela
authors.initials: M
authors.lastname: Villalobos-Comparan
authors.forename: Leonor
authors.initials: L
authors.lastname: Jacobo-Albavera
authors.forename: Salvador
authors.initials: S
authors.lastname: Ramírez-Jiménez
authors.forename: Martin
authors.initials: M
authors.lastname: Sikora
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Zhang
authors.forename: Terry D
authors.initials: TD
authors.lastname: Pape
authors.forename: Ma de Angeles
authors.initials: Mde A
authors.lastname: Granados-Silvestre
authors.forename: Isela
authors.initials: I
authors.lastname: Montufar-Robles
authors.forename: Ana M
authors.initials: AM
authors.lastname: Tito-Alvarez
authors.forename: Camilo
authors.initials: C
authors.lastname: Zurita-Salinas
authors.forename: José
authors.initials: J
authors.lastname: Bustos-Arriaga
authors.forename: Leticia
authors.initials: L
authors.lastname: Cedillo-Barrón
authors.forename: Celta
authors.initials: C
authors.lastname: Gómez-Trejo
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Barquera-Lozano
authors.forename: Joao P
authors.initials: JP
authors.lastname: Vieira-Filho
authors.forename: Julio
authors.initials: J
authors.lastname: Granados
authors.forename: Sandra
authors.initials: S
authors.lastname: Romero-Hidalgo
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vázquez
authors.forename: Antonio
authors.initials: A
authors.lastname: González-Martín
authors.forename: Amaya
authors.initials: A
authors.lastname: Gorostiza
authors.forename: Sandro L
authors.initials: SL
authors.lastname: Bonatto
authors.forename: Maricela
authors.initials: M
authors.lastname: Rodríguez-Cruz
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Teresa
authors.initials: T
authors.lastname: Tusié-Luna
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.forename: Ruben
authors.initials: R
authors.lastname: Lisker
authors.forename: Regina S
authors.initials: RS
authors.lastname: Moises
authors.forename: Marta
authors.initials: M
authors.lastname: Menjivar
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Salzano
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: M Cátira
authors.initials: MC
authors.lastname: Bortolini
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
authors.forename: Samuel
authors.initials: S
authors.lastname: Canizales-Quinteros
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology; D000328:Adult; D000483:Alleles; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005843:Geography; D006239:Haplotypes; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D012641:Selection, Genetic
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL