Evaluation of A2BP1 as an Obesity Gene Academic Article uri icon

  •  
  • Overview
  •  
  • Research
  •  
  • Identity
  •  
  • Additional Document Info
  •  
  • View All
  •  

abstract

  • 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. RESEARCH DESIGN AND 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.

authors

  • Ma, L
  • Hanson, RL
  • Traurig, MT
  • Muller, YL
  • Kaur, BP
  • Perez, JM
  • Meyre, David Jean-Claude
  • Fu, M
  • Korner, A
  • Franks, PW
  • Kiess, W
  • Kobes, S
  • Knowler, WC
  • Kovacs, P
  • Froguel, P
  • Shuldiner, AR
  • Bogardus, C
  • Baier, LJ

publication date

  • November 1, 2010

has subject area