Discovery of gene deletions and duplications associated with severe obesity

发现与严重肥胖相关的基因缺失和重复

• 批准号: 496538063
• 负责人: Dr. Ruth Hanssen
• 金额: --
• 依托单位: Max-Planck-Institut für Stoffwechselforschung
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/496538063?language=en
• 关键词: Discovery; gene; deletions; duplications; associated

The rising prevalence of obesity is driven by environmental factors including the consumption of high-calorie foods and reduced levels of physical activity. However, family, twin, and adoption studies have consistently demonstrated that 40%–70% of the variation in body weight between people living in a given environment can be explained by genetic factors. Over the last 20 years, sequencing of candidate genes has led to the identification of monogenic forms of severe obesity which impact on the function of proteins involved in the central leptin-melanocortin pathway. These findings have paved the way for stratified therapy as seen with the treatment of congenital leptin deficiency by recombinant leptin. However, a substantial proportion of the heritability of human obesity has yet to be explained. The aim of this project is to explore the contribution of copy number variants (CNVs) to the development of severe obesity. This project builds on previous work where the Farooqi team demonstrated that deletion of chromosome 16p11.2 was associated with highly penetrant severe early-onset obesity and severe insulin resistance. As Sh2b1 knockout mice develop obesity and insulin resistance, it was suggested that disruption of the SH2B1 gene was responsible for the obesity of deletion carriers. This was verified in further human genetic studies which identified multiple missense mutations in SH2B1 which impaired signaling by molecules involved in energy balance. Together these findings have paved the way for patients with both deletions and coding mutations to be enrolled in clinical trials of MC4 Receptor agonist Setmelanotide. In this project, my aim is to discover new obesity genes by interrogating deletions and duplications in large cohorts (cohort of the Genetics of Obesity Study with ~7000 people) with severe obesity available in the Farooqi lab in Cambridge, UK. Finding the genes whose disruption causes obesity can provide a diagnosis for patients, insights into the mechanisms underlying the development of obesity and can identify targets for weight loss therapy.

肥胖症患病率的上升是由环境因素驱动的，包括高热量食物的消费和身体活动水平的降低。然而，家庭、双胞胎和收养研究一致表明，生活在特定环境中的人之间的体重差异有40%-70%可以由遗传因素解释。在过去的20年中，候选基因的测序已经导致了严重肥胖的单基因形式的鉴定，其影响参与中枢瘦素-黑皮质素途径的蛋白质的功能。这些发现为分层治疗铺平了道路，如重组瘦素治疗先天性瘦素缺乏症。然而，人类肥胖的遗传性的很大一部分尚未得到解释。该项目的目的是探索拷贝数变异（CNVs）对严重肥胖发展的贡献。该项目建立在Farooqi团队先前的工作基础上，该工作表明染色体16p11.2的缺失与高度渗透性严重早发性肥胖和严重胰岛素抵抗相关。由于Sh 2B 1基因敲除小鼠发生肥胖和胰岛素抵抗，因此认为SH 2B 1基因的破坏是缺失携带者肥胖的原因。这在进一步的人类遗传学研究中得到了证实，这些研究发现了SH 2B 1中的多个错义突变，这些突变损害了参与能量平衡的分子的信号传导。这些发现为缺失和编码突变的患者参与MC 4受体激动剂Setmelanotide的临床试验铺平了道路。在这个项目中，我的目标是通过询问英国剑桥Farooqi实验室中严重肥胖的大型队列（肥胖遗传学研究队列，约7000人）中的缺失和重复来发现新的肥胖基因。找到导致肥胖的基因可以为患者提供诊断，深入了解肥胖发展的机制，并可以确定减肥治疗的目标。