Lack of support for the association between GAD2 polymorphisms and severe human obesity.
Lack of support for the association between GAD2 polymorphisms and severe human obesity.
复制标题
DOI：
10.1371/journal.pbio.0030315
复制
发表时间：
2005-09
期刊：
影响因子：
9.8
通讯作者：
Vaisse C
中科院分区：
文献类型：
--
作者：
Swarbrick MM;Waldenmaier B;Pennacchio LA;Lind DL;Cavazos MM;Geller F;Merriman R;Ustaszewska A;Malloy M;Scherag A;Hsueh WC;Rief W;Mauvais-Jarvis F;Pullinger CR;Kane JP;Dent R;McPherson R;Kwok PY;Hinney A;Hebebrand J;Vaisse C
常见遗传变异与肥胖等慢性人类疾病之间的关联可能对这些疾病的预测，预防和治疗产生深远的影响。然而，这种关联的明确证据需要独立复制最初的阳性结果。最近，发现谷氨酸脱羧酶2（GAD 2）内的三个（−243 A>G，+61450 C>A和+83897 T>A）单核苷酸多态性（SNP）与III类肥胖（体重指数> 40 kg/m2）相关。在188个家庭（612人）分离的条件下，和575例和646瘦对照的病例对照研究中观察到的关联。还提供了支持其中一个SNP（−243 A>G）的病理生理作用的功能数据。基因GAD 2编码谷氨酸脱羧酶-GAD 65的65-kDa亚基。在本研究中，我们试图在更大的个体群体中复制这种关联，并扩展−243 A>G SNP的功能研究。在2，359人组成的693个德国核心家庭严重，早发性肥胖症，我们没有发现三个GAD 2 SNPs和肥胖之间的关系的证据，无论是单体型或单体型研究。在两项独立的病例对照研究（共680例III级肥胖病例和1,186例瘦对照）中，合并样本中−243 A>G SNP与肥胖之间没有显著关系（OR = 0.99，95%CI 0.83-1.18，p = 0.89）。这些阴性结果在荟萃分析中得到了概括，纳入了所有已发表的− 243 G等位基因与III类肥胖之间相关性的数据，在1，252例III类肥胖病例和1，800例瘦对照的总样本中，OR为1.11（95%CI 0.90-1.36，p = 0.28）。此外，对包含GAD 2基因座的常见单倍型的分析显示，在患有这种疾病的家庭中，与严重肥胖无关。我们还获得了-243 A>G SNP的功能数据，但该数据不支持该变体在肥胖中的病理生理作用。在GAD 2和严重肥胖的背景下，还讨论了涉及常见变异和复杂疾病的关联研究中的潜在混杂变量（检测适度遗传效应的低功效、边缘数据的过度解释、人群分层和生物学可接受性）。一项涉及多个人群的大型遗传研究无法复制先前将GAD 2基因变异与肥胖易感性联系起来的发现。
The demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention, and treatment of these conditions. Unequivocal proof of such an association, however, requires independent replication of initial positive findings. Recently, three (−243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 188 families (612 individuals) segregating the condition, and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (−243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase—GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the −243 A>G SNP. Among 2,359 individuals comprising 693 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the −243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83–1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the −243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90–1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data for the −243 A>G SNP that does not support a pathophysiological role for this variant in obesity. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, overinterpretation of marginal data, population stratification, and biological plausibility) are also discussed in the context of GAD2 and severe obesity. A large genetic study involving multiple populations is not able to replicate previous findings linking variation in the GAD2 gene to susceptibility to obesity.
登录
查看更多内容
影响因子：
158.5
作者：
Calle, EE;Thun, MJ;Heath, CW
通讯作者：
Heath, CW
影响因子：
9.8
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
通讯作者：
Froguel P
影响因子：
120.7
作者：
Flegal, KM;Carroll, MD;Johnson, CL
通讯作者：
Johnson, CL
影响因子：
5.8
作者：
Hinney, A;Ziegler, A;Hebebrand, J
通讯作者：
Hebebrand, J
影响因子：
9.8
作者：
Martin, ER;Monks, SA;Kaplan, NL
通讯作者：
Kaplan, NL