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Plos Biology : Gad2 on Chromosome 10P12 is a Candidate Gene for Human Obesity, Volume 1

By Bell, John

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Book Id: WPLBN0003921948
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Gad2 on Chromosome 10P12 is a Candidate Gene for Human Obesity, Volume 1  
Author: Bell, John
Volume: Volume 1
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Publication Date:
Publisher: Plos


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Bell, J. (n.d.). Plos Biology : Gad2 on Chromosome 10P12 is a Candidate Gene for Human Obesity, Volume 1. Retrieved from

Description : 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 c-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) þ61450 C.A and þ83897 T.A (OR ¼ 0.81, 95% CI [0.681–0.972], p ¼ 0.0049) and an at-risk SNP ( 243 A.G) for morbid obesity (OR ¼ 1.3, 95% CI [1.053–1.585], p ¼ 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP þ61450 C.A and þ83897 T.A haplotype (v2 ¼ 7.637, p ¼ 0.02). In the murine insulinoma cell line bTC3, 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 (p¼0.007) and disinhibition scores (p¼0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic b cells, we analyzed GAD65 antibody level as a marker of bcell activity and of insulin secretion. In the control group, 243 A.G, þ61450 C.A, and þ83897 T.A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNPþ83897 T.A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of bcell function (p ¼ 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.


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