PTPRG

今天上午10点，~300位朋友已预约！药时代路演第三期 | 抗体领域龙头企业优质系列双抗对外授权撰文丨王聪如今，肥胖已成为一个全球性问题，影响着6.5亿成年人和1.24亿儿童和青少年。更重要的是，肥胖与死亡率和发病率增加以及许多合并症有关，例如心血管疾病和2型糖尿病（T2D），并构成巨大的健康负担。女性的肥胖发病率高于男性，女性往往有更多的体脂，这些体脂优先以皮下脂肪的形式储存在下半身，而男性更容易在腹部区域积累内脏脂肪。肥胖的这些性别差异影响了几种肥胖相关合并症的风险，如高血压和糖尿病。然而，针对不同性别的肥胖研究并不多，大多数基因研究只是根据性别进行调整，而不是分别分析男性和女性的数据。据估计，体重指数（BMI）的个体间差异约有40%-70%可归因于遗传因素。之前的大规模研究已经确定了900多个与成年人BMI相关的遗传位点。这些遗传变异虽然很常见，但大多数都位于非编码区，总的来说只能解释成年人BMI个体间差异的6%。体重指数（BMI）是衡量超重（BMI≥25kg/m2）和肥胖（BMI≥30kg/m2）的最常见指标。最近，全外显子组测序（WES）开始应用于大规模人群研究，使得对疾病和相关性状中罕见的编码基因变异的评估成为可能。2023年8月2日，剑桥大学的研究人员在 Cell 子刊 Cell Genomics 上发表了题为：Large-scale exome sequence analysis identifies sex- and age-specific determinants of obesity 的研究论文。这项针对40多万成年人的最新研究表明，某些基因对肥胖风险的影响取决于个体的性别和年龄。这项针对近42万人的大规模全外显子组测序（WES）数据分析，确定了与成年女性体重指数（BMI）增加相关的3个基因——DIDO1、PTPRG 和 SLC12A5，以及与成年男性体重指数（BMI）增加相关的1个基因——SLTM。它们的罕见杂合性功能缺失突变会显著增加成年人BMI，效应量高达8kg/m2。该研究还发现了两个基因与儿童期体型相关的罕见基因变异 OBSCN 和 MADD，携带 OBSCN 变异者与儿童期易肥胖，携带 MADD 变异儿童期体型较小，成年后不太可能肥胖。对这些基因的功能分析显示，神经元死亡、细胞凋亡和DNA损伤反应机制在整个生命历程中对肥胖的易感性中起作用。这些发现强调了在肥胖的基因调控中考虑性别特异性和生命历程效应的重要性。基因和饮食等环境因素之间的相互作用决定了人们的体重和体型。在这项最新研究中，研究团队对来自英国生物样本库（UK Biobank）中近42万名成年参与者的全外显子组测序（WES）数据进行了分析，进而研究男性和女性中与体重指数（BMI）相关的基因变异，以及与参与者在10岁时报告的体型相关的基因变异。分析结果显示，DIDO1、PTPRG、SLC12A5 这三个基因的罕见功能缺失突变与成年女性较高的BMI有关，而 SLTM 基因变异则与成年男性较高的BMI有关。特别是，超过80%携带 DIDO1 和 SLC12A5 基因变异的女性患有肥胖症。此外，DIDO1 基因变异与更高的睾酮（一种雄性激素）水平和更大的腰臀比有关，而这两者都是糖尿病和心脏病等肥胖相关疾病的风险因素。该研究还表明，携带 SLC12A5 基因变异的女性患2型糖尿病的风险更高。基于年龄的分析强调了与儿童肥胖和成人高BMI相关的几个基因，包括 MC4R 和CALCR。同时还发现了两个新的与儿童体型有关的基因——OBSCN 和 MADD。携带 OBSCN 基因变异的人更有可能在儿童时期肥胖，而携带 MADD 基因变异的人在儿童时期则体型较小，且成年后不太可能肥胖。肥胖在全世界都已成为一个日益严重的问题。仅在美国，2019年因肥胖产生的医疗费用就超过1700亿美元。据世界卫生组织（WHO）的数据，2016年全世界约有6.5亿成年人肥胖。像这样的大规模人口研究可以阐明影响肥胖的重要通路，并有望成为治疗肥胖的药物的靶标。该论文的通讯作者、剑桥大学遗传学家 John Perry 教授表示，该研究发现的一些肥胖相关基因中有几个与DNA损伤反应和细胞死亡有关。目前还没有很好地理解DNA损伤反应是如何影响体型的。但这些发现给了我们一个提示，DNA损伤这一重要生物过程的变异可能在肥胖的病因中发挥作用。他还表示，希望这项研究能揭示新的生物学通路，在将来能为发现治疗肥胖的新药铺平道路。此外，研究团队计划在更大、更多样化的人群中重复这项研究。他们还计划在动物中验证这些基因与肥胖之间的关系。论文链接：https://doi.org/10.1016/j.xgen.2023.100362封面图来源：123rf精彩推荐PHDI 2023 倒计时1个月丨30+业内大咖云集制药产业数智化峰会最后的「退货」，EQRx把翰森的阿美替尼也放弃了...美国研发出能杀死所有实体瘤的药物，是不是真的？药时代路演第三期 | 抗体领域龙头企业优质系列双抗对外授权药研之“星”，等你来挑战点击这里，与药时代一起快乐学习！

From influencing how our body stores fat to how our brain regulates appetite, hundreds of genes, along with environmental factors, collectively determine our weight and body size. Now, researchers add several genes, which appear to affect obesity risk in certain sexes and ages, to that list. The study may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease. From influencing how our body stores fat to how our brain regulates appetite, hundreds of genes, along with environmental factors, collectively determine our weight and body size. Now, researchers add several genes, which appear to affect obesity risk in certain sexes and ages, to that list. The study, published on August 2 in the journal Cell Genomics, may shed light on new biological pathways that underlie obesity and highlight how sex and age contribute to health and disease. "There are a million and one reasons why we should be thinking about sex, age, and other specific mechanisms rather than just lumping everyone together and assuming that disease mechanism works the same way for everyone," says senior author John Perry, a geneticist and professor at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, U.K. "We're not expecting people to have completely different biology, but you can imagine things like hormones and physiology can contribute to specific risks." To untangle sex's role in obesity risk, the research team sequenced the exome -- the protein-coding part of the genome -- of 414,032 adults from the UK Biobank study. They looked at variants, or mutations, within genes associated with body mass index (BMI) in men and women, respectively. Based on height and weight, BMI is an estimated measurement of obesity. The search turned up five genes influencing BMI in women and two in men. Among them, faulty variants of three genes -- DIDO1, PTPRG, and SLC12A5 -- are linked to higher BMI in women, up to nearly 8 kg/m² more, while having no effect on men. Over 80% of the women with DIDO1 and SLC12A5 variants had obesity, as approximated by their BMI. Individuals carrying DIDO1 variants had stronger associations with higher testosterone levels and increased waist-to-hip ratio, both risk indicators for obesity-related complications like diabetes and heart disease. Others with SLC12A5 variants had higher odds of having type 2 diabetes compared with non-carriers. These findings highlight previously unexplored genes that are implicated in the development of obesity in women but not men. Perry and his colleague then repeated their method to look for age-specific factors by searching for gene variants associated with childhood body size based on participants' recollections. They identified two genes, OBSCN and MADD, that were not previously linked to childhood body size and fat. While carriers of OBSCN variants had higher odds of having higher weight as a child, MADD variant carriers were associated with smaller body sizes. In addition, the genetic variants acting on MADD had no association with adult obesity risk, highlighting age-specific effects on body size. "What's quite surprising is that if you look at the function of some of these genes that we identified, several are clearly involved in DNA damage response and cell death," says Perry. Obesity is a brain-related disorder, whereas biological and environmental factors act to influence appetite. "There's currently no well-understood biological paradigm for how DNA damage response would influence body size. These findings have given us a signpost to suggest variation in this important biological process may play a role in the etiology of obesity." Next, the research team hopes to replicate the study in a larger and more diverse population. They also plan to study the genes in animals to peer into their function and relationship with obesity. "We're at the very earliest stages of identifying interesting biology," says Perry. "We hope the study can reveal new biological pathways that may one day pave the way to new drug discovery for obesity."