Prokopenko Inga, Poon Wenny, Mägi Reedik, Prasad B Rashmi, Salehi S Albert, Almgren Peter, Osmark Peter, Bouatia-Naji Nabila, Wierup Nils, Fall Tove, Stančáková Alena, Barker Adam, Lagou Vasiliki, Osmond Clive, Xie Weijia, Lahti Jari, Jackson Anne U, Cheng Yu-Ching, Liu Jie, O'Connell Jeffrey R, Blomstedt Paul A, Fadista Joao, Alkayyali Sami, Dayeh Tasnim, Ahlqvist Emma, Taneera Jalal, Lecoeur Cecile, Kumar Ashish, Hansson Ola, Hansson Karin, Voight Benjamin F, Kang Hyun Min, Levy-Marchal Claire, Vatin Vincent, Palotie Aarno, Syvänen Ann-Christine, Mari Andrea, Weedon Michael N, Loos Ruth J F, Ong Ken K, Nilsson Peter, Isomaa Bo, Tuomi Tiinamaija, Wareham Nicholas J, Stumvoll Michael, Widen Elisabeth, Lakka Timo A, Langenberg Claudia, Tönjes Anke, Rauramaa Rainer, Kuusisto Johanna, Frayling Timothy M, Froguel Philippe, Walker Mark, Eriksson Johan G, Ling Charlotte, Kovacs Peter, Ingelsson Erik, McCarthy Mark I, Shuldiner Alan R, Silver Kristi D, Laakso Markku, Groop Leif, Lyssenko Valeriya
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Department of Clinical Science, Diabetes & Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
PLoS Genet. 2014 Apr 3;10(4):e1004235. doi: 10.1371/journal.pgen.1004235. eCollection 2014 Apr.
Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.
在一项全基因组关联研究（GWAS）荟萃分析中，生长因子受体结合蛋白10（GRB10）基因的变异若从父亲遗传而来，与葡萄糖刺激的胰岛素分泌减少及2型糖尿病（T2D）风险增加相关，但从母亲遗传时却会莫名降低空腹血糖。GRB10是胰岛素信号传导的负调节因子，且在不同组织中以亲本来源的方式印记。在人胰岛中敲低GRB10显示胰岛素和胰高血糖素分泌减少，这与胰岛素敏感性的变化一起，可能解释了尽管胰岛素分泌减少但血糖却出现矛盾性降低的现象。总之，这些发现表明GRB10的组织特异性甲基化以及可能的印记能够影响葡萄糖代谢并促成T2D的发病机制。这些数据还强调了在基因研究中需要考虑风险等位基因是从母亲还是父亲遗传而来。
