A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans.
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.
Acuña-Alonzo
Víctor
V
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.
Flores-Dorantes
Teresa
T
Kruit
Janine K
JK
Villarreal-Molina
Teresa
T
Arellano-Campos
Olimpia
O
Hünemeier
Tábita
T
Moreno-Estrada
Andrés
A
Ortiz-López
Ma Guadalupe
MG
Villamil-Ramírez
Hugo
H
León-Mimila
Paola
P
Villalobos-Comparan
Marisela
M
Jacobo-Albavera
Leonor
L
Ramírez-Jiménez
Salvador
S
Sikora
Martin
M
Zhang
Lin-Hua
LH
Pape
Terry D
TD
Granados-Silvestre
Ma de Angeles
Mde A
Montufar-Robles
Isela
I
Tito-Alvarez
Ana M
AM
Zurita-Salinas
Camilo
C
Bustos-Arriaga
José
J
Cedillo-Barrón
Leticia
L
Gómez-Trejo
Celta
C
Barquera-Lozano
Rodrigo
R
Vieira-Filho
Joao P
JP
Granados
Julio
J
Romero-Hidalgo
Sandra
S
Huertas-Vázquez
Adriana
A
González-Martín
Antonio
A
Gorostiza
Amaya
A
Bonatto
Sandro L
SL
Rodríguez-Cruz
Maricela
M
Wang
Li
L
Tusié-Luna
Teresa
T
Aguilar-Salinas
Carlos A
CA
Lisker
Ruben
R
Moises
Regina S
RS
Menjivar
Marta
M
Salzano
Francisco M
FM
Knowler
William C
WC
Bortolini
M Cátira
MC
Hayden
Michael R
MR
Baier
Leslie J
LJ
Canizales-Quinteros
Samuel
S
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
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL