GAD2 on chromosome 10p12 is a candidate gene for human obesity

Boutin, Philippe, Dina, Christian, Vasseur, Francis, Dubois, Severine, Corset, Laetitia, Seron, Karen, Bekris, Lynn, Cabellon, Janice, Neve, Bernadette, Vasseur-delannoy, Valerie, Chikri, Mohamed, Charles, M. Aline, Clement, Karine, Lernmark, Ake and Froguel, Philippe 2003, GAD2 on chromosome 10p12 is a candidate gene for human obesity, PLOS biology, vol. 1, no. 3, pp. 361-371.

Attached Files
Name Description MIMEType Size Downloads

Title GAD2 on chromosome 10p12 is a candidate gene for human obesity
Author(s) Boutin, Philippe
Dina, Christian
Vasseur, Francis
Dubois, Severine
Corset, Laetitia
Seron, Karen
Bekris, Lynn
Cabellon, Janice
Neve, Bernadette
Vasseur-delannoy, Valerie
Chikri, Mohamed
Charles, M. Aline
Clement, Karine
Lernmark, Ake
Froguel, Philippe
Journal name PLOS biology
Volume number 1
Issue number 3
Start page 361
End page 371
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2003
ISSN 1544-9173
1545-7885
Summary The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11–12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of γ-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681–0.972], p = 0.0049) and an at-risk SNP (−243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053–1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, the G at-risk allele of SNP −243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The −243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic β cells, we analyzed GAD65 antibody level as a marker of β-cell activity and of insulin secretion. In the control group, −243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of β-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity.
Language eng
Field of Research 060412 Quantitative Genetics (incl Disease and Trait Mapping Genetics)
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2003, Boutin et al.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30009189

Document type: Journal Article
Collection: School of Exercise and Nutrition Sciences
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 70 times in TR Web of Science
Scopus Citation Count Cited 87 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 821 Abstract Views, 0 File Downloads  -  Detailed Statistics
Created: Mon, 13 Oct 2008, 15:53:47 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.