TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition
TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition
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DOI：
10.1093/hmg/ddl204
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发表时间：
2006-09-15
影响因子：
3.5
通讯作者：
Shattuck, Donna
中科院分区：
文献类型：
--
作者：
Stone, Steven;Abkevich, Victor;Shattuck, Donna
肥胖易感性的分子病因学在很大程度上是未知的。在这里，我们提出的证据表明，TBC 1D 1的遗传变异赋予女性严重肥胖的风险。我们在TBC 1D 1中发现了一个编码变体（R125 W），该变体与4p 15 -14相关肥胖谱系中的疾病分离。在来自具有最强连锁证据的家系的病例中，该变异与肥胖显著相关（P=0.000007），携带R125 W的染色体占最初将4p 15 -14与该疾病联系起来的大多数证据。此外，通过选择分离R125 W与肥胖的家庭，我们能够在4 q34 -35产生高度显着的肥胖易感基因座的连锁证据。这一结果提供了额外的和确认的证据，R125 W影响肥胖易感性，界定了肥胖基因在4 q34 -35的位置，并确定了影响肥胖易感性风险的基因/基因相互作用。最后，尽管TBC 1D 1的功能尚不清楚，但该蛋白质在结构上与已知的胰岛素介导的Glut 4易位调节剂相似。
The molecular etiology of obesity predisposition is largely unknown. Here, we present evidence that genetic variation in TBC1D1 confers risk for severe obesity in females. We identified a coding variant (R125W) in TBC1D1 that segregated with the disease in 4p15-14-linked obesity pedigrees. In cases derived from pedigrees with the strongest linkage evidence, the variant was significantly associated with obesity (P=0.000007) and chromosomes carrying R125W accounted for the majority of the evidence that originally linked 4p15-14 with the disease. In addition, by selecting families that segregated R125W with obesity, we were able to generate highly significant linkage evidence for an obesity predisposition locus at 4q34-35. This result provides additional and confirming evidence that R125W affects obesity susceptibility, delimits the location of an obesity gene at 4q34-35 and identifies a gene/gene interaction that influences the risk for obesity predisposition. Finally, although the function of TBC1D1 is unknown, the protein is structurally similar to a known regulator of insulin-mediated Glut4 translocation.