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. 2003 Dec;1(3):E68.
doi: 10.1371/journal.pbio.0000068. Epub 2003 Nov 3.

"VSports注册入口" GAD2 on chromosome 10p12 is a candidate gene for human obesity

Philippe Boutin  1 , Christian Dina, Francis Vasseur, Séverine Dubois, Laetitia Corset, Karin Séron, Lynn Bekris, Janice Cabellon, Bernadette Neve, Valérie Vasseur-Delannoy, Mohamed Chikri, M Aline Charles, Karine Clement, Ake Lernmark, Philippe Froguel
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GAD2 on chromosome 10p12 is a candidate gene for human obesity

Philippe Boutin et al. PLoS Biol. 2003 Dec.

Abstract

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 gamma-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 (chi(2) = 7. 637, p = 0. 02) VSports手机版. In the murine insulinoma cell line betaTC3, 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 beta cells, we analyzed GAD65 antibody level as a marker of beta-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 beta-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. .

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Conflict of interest statement

The authors have declared that no conflicts of interest exist.

Figures

Figure 1
Figure 1. Mapping of Chromosome 10p and the GAD2 Gene
(A) Fine mapping of the Chromosome 10p locus between markers D10S548 and D10S220 in 188 nuclear families (620 individuals). Multipoint analysis for obesity phenotype. (B) SNP map of the GAD2 gene. Positions were assigned according the location to the A of the ATG. The 15 SNPs selected for association studies are indicated in red. See also Table 1.
Figure 2
Figure 2. Pairwise LD between SNPs of GAD2 and MYO3 Genes in the French Obese Population
Pairwise LD between SNPs is measured by triangles (color scale). Regions of high and low LD are represented by red and blue shading, respectively. The graph is not to scale; indeed, the SNPs are equidistant to highlight the detailed pattern of LD.
Figure 3
Figure 3. Effect of the −243 A>G , −1600 G>A, and −2004 A>T SNPs on Transcriptional Activity
G, A, and T alleles at −243 A>G, −1600 G>A, and −2004 A>T SNPs were generated into the wild-type construct (wt). βTC3 cells were transfected with equivalent amounts of pGL3, wild-type, Gad-2004T, Gad-1600A, and Gad-243G constructs. pRLTK was cotransfected with each construct. Luciferase and Renilla activities were assayed and normalized. Each experiment was performed in duplicate and replicated five times. A 6-fold increase of transcriptional activity was observed for the Gad-243 as compared to the wild-type construct.
Figure 4
Figure 4. EMSA of the the −243 A>G Polymorphism with βTC3 Nuclear Proteins
Specific complex formation is indicated by an arrow. Lanes (−) are radiolabeled probes without nuclear extract. βTC3 nuclear proteins have an higher affinity for the G allele variant than for the A allele at SNP −243 A>G.
Figure 5
Figure 5. Association Studies of the −243 A>G Variant with Food Intake Behavior Parameters in Morbidly Obese Patients
The three stable factors—cognitive restraint of eating, disinibition, and hunger—were assessed in 464 morbidly obese patients to fill in the TFEQ established by Stunkard and Messick (1985). Mean score values ± SD for each genotype are represented.
Figure 6
Figure 6. Ln GAD65Ab Levels Adjusted for Age and BMI According to the Genotypes at SNPs −243 A>G, +61450 C>A, and +83897 T>A
Mean level values ± SD are displayed for each genotype. Wild-type are AA, CC, TT; heterozygous are AG, CA, TA; and homozygous are GG, AA, AA, respectively, for each SNP. (A) Nonobese normoglycemic subjects. (B) Morbidly obese patients.
Figure 7
Figure 7. Fasting Insulin and HOMA
Fasting insulin (A) and assessment of HOMA-B% (B) in 376 nonobese normoglycemic subjects according to the genotypes at SNPs −243 A>G, +61450 C>A, and +83897 T>A. Mean level values ± SD are displayed for each genotype. Wild-type are AA, CC, TT; heterozygous are AG, CA, TA; and homozygous are GG, AA, AA, respectively, for each SNP.
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Comment in

  • Replication publication. (V体育平台登录)
    Patterson M, Cardon L. Patterson M, et al. PLoS Biol. 2005 Sep;3(9):e327. doi: 10.1371/journal.pbio.0030327. Epub 2005 Sep 13. PLoS Biol. 2005. PMID: 16149852 Free PMC article. No abstract available.

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