Evaluation of A2BP1 as an Obesity Gene

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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 x 10(-7)) and obesity in French Caucasian adult (rs4786847, P = 1.9 x 10(-10)) and children (rs8054147, P = 9.2 x 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. Diabetes 59:2837-2845, 2010

Details

Authors
  • Lijun Ma
  • Robert L. Hanson
  • Michael T. Traurig
  • Yunhua L. Muller
  • Bakhshish P. Kaur
  • Jessica M. Perez
  • David Meyre
  • Mao Fu
  • Antje Koerner
  • Paul Franks
  • Wieland Kiess
  • Sayuko Kobes
  • William C. Knowler
  • Peter Kovacs
  • Philippe Froguel
  • Alan R. Shuldiner
  • Clifton Bogardus
  • Leslie J. Baler
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)2837-2845
JournalDiabetes
Volume59
Issue number11
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes