Evaluation of A2BP1 as an obesity gene.
OBJECTIVE
A genome-wide association study (GWAS) in Pima Indians (n = 413) identified variation in the ataxin-2 binding protein 1 gene (A2BP1) that was associated with percent body fat. On the basis of this association and the obese phenotype of ataxin-2 knockout mice, A2BP1 was genetically and functionally analyzed to assess its potential role in human obesity.


METHODS
Variants spanning A2BP1 were genotyped in a population-based sample of 3,234 full-heritage Pima Indians, 2,843 of whom were not part of the initial GWAS study and therefore could serve as a sample to assess replication. Published GWAS data across A2BP1 were additionally analyzed in French adult (n = 1,426) and children case/control subjects (n = 1,392) (Meyre et al. Nat Genet 2009;41:157-159). Selected variants were genotyped in two additional samples of Caucasians (Amish, n = 1,149, and German children case/control subjects, n = 998) and one additional Native American (n = 2,531) sample. Small interfering RNA was used to knockdown A2bp1 message levels in mouse embryonic hypothalamus cells.


RESULTS
No single variant in A2BP1 was reproducibly associated with obesity across the different populations. However, different variants within intron 1 of A2BP1 were associated with BMI in full-heritage Pima Indians (rs10500331, P = 1.9 × 10(-7)) and obesity in French Caucasian adult (rs4786847, P = 1.9 × 10(-10)) and children (rs8054147, P = 9.2 × 10(-6)) case/control subjects. Reduction of A2bp1 in mouse embryonic hypothalamus cells decreased expression of Atxn2, Insr, and Mc4r.


CONCLUSIONS
Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway.
Ma
Lijun
L
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
Hanson
Robert L
RL
Traurig
Michael T
MT
Muller
Yunhua L
YL
Kaur
Bakhshish P
BP
Perez
Jessica M
JM
Meyre
David
D
Fu
Mao
M
Körner
Antje
A
Franks
Paul W
PW
Kiess
Wieland
W
Kobes
Sayuko
S
Knowler
William C
WC
Kovacs
Peter
P
Froguel
Philippe
P
Shuldiner
Alan R
AR
Bogardus
Clifton
C
Baier
Leslie J
LJ
D000328:Adult; D000818:Animals; D001823:Body Composition; D015992:Body Mass Index; D002648:Child; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005602:France; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D035781:Siblings
D018076:DNA, Complementary; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C465036:Rbfox1 protein, mouse