Stone Steven, Abkevich Victor, Russell Deanna L, Riley Robyn, Timms Kirsten, Tran Thanh, Trem Deborah, Frank David, Jammulapati Srikanth, Neff Chris D, Iliev Diana, Gress Richard, He Gongping, Frech Georges C, Adams Ted D, Skolnick Mark H, Lanchbury Jerry S, Gutin Alexander, Hunt Steven C, Shattuck Donna
Myriad Genetics, Inc., Salt City, UT 84108, USA.
Hum Mol Genet. 2006 Sep 15;15(18):2709-20. doi: 10.1093/hmg/ddl204. Epub 2006 Aug 7.
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.
肥胖易感性的分子病因在很大程度上尚不清楚。在此，我们提供证据表明，TBC1D1基因的遗传变异会增加女性患严重肥胖症的风险。我们在TBC1D1中鉴定出一个编码变体（R125W），该变体在4p15 - 14连锁的肥胖家系中与疾病共分离。在来自连锁证据最强的家系的病例中，该变体与肥胖显著相关（P = 0.000007），携带R125W的染色体占最初将4p15 - 14与该疾病联系起来的大部分证据。此外，通过选择R125W与肥胖共分离的家系，我们能够为4q34 - 35处的肥胖易感性位点生成高度显著的连锁证据。这一结果提供了额外的佐证，证明R125W影响肥胖易感性，确定了4q34 - 35处肥胖基因的位置，并识别出一种影响肥胖易感性风险的基因/基因相互作用。最后，尽管TBC1D1的功能尚不清楚，但该蛋白在结构上与已知的胰岛素介导的Glut4易位调节因子相似。
