GAD2 on chromosome 10p12 is a candidate gene for human obesity.
GAD2 on chromosome 10p12 is a candidate gene for human obesity.
复制标题
DOI：
10.1371/journal.pbio.0000068
复制
发表时间：
2003-12
期刊：
影响因子：
9.8
通讯作者：
Froguel P
中科院分区：
文献类型：
--
作者：
Boutin P;Dina C;Vasseur F;Dubois S;Corset L;Séron K;Bekris L;Cabellon J;Neve B;Vasseur-Delannoy V;Chikri M;Charles MA;Clement K;Lernmark A;Froguel P
编码谷氨酸脱羧酶（GAD 65）的基因GAD 2是染色体10 p11 -12上的肥胖症的位置候选基因，染色体10 p11 -12是四个独立种族人群中病态肥胖症的易感位点。GAD 65催化γ-氨基丁酸（GABA）的形成，γ-氨基丁酸与室旁核中的神经肽Y相互作用以促进刺激食物摄入。病例对照研究（575名病态肥胖者和646名对照受试者）分析GAD 2变异体发现了保护性单倍型，包括单核苷酸多态性（SNP）+61450 C>A和+83897 T>A的最常见等位基因。（OR = 0.81，95%CI [0.681-0.972]，p = 0.0049）和病态肥胖的风险SNP（−243 A>G）（OR = 1.3，95%CI [1.053-1.585]，p = 0.014）。此外，基于家庭的分析证实SNP +61450 C>A和+83897 T>A单倍型与肥胖相关（χ2 = 7.637，p = 0.02）。在小鼠胰岛素瘤细胞系β TC 3中，SNP −243 A>G的G风险等位基因使GAD 2启动子活性增加了6倍（p < 0.0001），并诱导对核提取物的亲和力增加了6倍。根据Stunkard三因素饮食问卷的评估，-243 A>G SNP与较高的饥饿评分（p = 0.007）和去抑制评分（p = 0.028）相关。由于GAD 2在胰腺β细胞中高度表达，我们分析了GAD 65抗体水平作为β细胞活性和胰岛素分泌的标志物。在对照组中，−243 A>G、+61450 C>A和+83897 T>A SNP与较低的GAD 65自身抗体水平相关（p值分别为0.003、0.047和0.006）。SNP +83897 T>A与较低的空腹胰岛素和胰岛素分泌相关，如通过β细胞功能的HOMA-B%稳态模型所评估的（分别为p = 0.009和0.01）。这些数据支持GABA在人类中的食欲促进作用的假设，以及参与GABA代谢的基因在调节食物摄入和病态肥胖症的发展中的贡献。一项大型病例对照研究、基于家族的遗传分析和功能数据表明，GAD 2基因的变异影响饮食行为和胰岛素代谢。
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. A large case-control study, family-based genetic analyses, and functional data suggest that variation in the GAD2 gene affects eating behavior and insulin metabolism
登录
查看更多内容
影响因子：
9.8
作者：
Bulik, CM;Devlin, B;Kaye, WH
通讯作者：
Kaye, WH
DOI：
10.2165/00129785-200202030-00003
发表时间：
2002-01-01
期刊：
American journal of pharmacogenomics : genomics-related research in drug development and clinical practice
影响因子：
--
作者：
Clement, Karine;Boutin, Philippe;Froguel, Philippe
通讯作者：
Froguel, Philippe
影响因子：
2.9
作者：
DENBOW, DM
通讯作者：
DENBOW, DM
影响因子：
9.8
作者：
Martin, ER;Monks, SA;Kaplan, NL
通讯作者：
Kaplan, NL
影响因子：
30.8
作者：
Horikawa, Y;Oda, N;Bell, GI
通讯作者：
Bell, GI