Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, USA.
Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Mol Diagn Ther. 2020 Dec;24(6):653-663. doi: 10.1007/s40291-020-00496-1. Epub 2020 Oct 1.
Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes substantially to mortality in the United States by increasing the risk for type 2 diabetes, cardiovascular-related diseases, and other comorbidities. Despite environmental changes over past decades, including increases in high-calorie foods and sedentary lifestyles, there is very clear evidence of a genetic predisposition to obesity risk. Childhood obesity cases can be categorized in one of two ways: syndromic or non-syndromic. Syndromic obesity includes disorders such as Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome. Non-syndromic cases of obesity can be further separated into rarer instances of monogenic obesity and much more common forms of polygenic obesity. The advent of genome-wide association studies (GWAS) and next-generation sequencing has driven significant advances in our understanding of the genetic contribution to childhood obesity. Many rare and common genetic variants have been shown to contribute to the heritability in obesity, although the molecular mechanisms underlying most of these variants remain unclear. An important caveat of GWAS efforts is that they do not strictly represent gene target discoveries, rather simply the uncovering of robust genetic signals. One clear example of this is with progress in understanding the key obesity signal harbored within an intronic region of the FTO gene. It has been shown that the non-coding region in which the variant actually resides in fact influences the expression of genes distal to FTO instead, specifically IRX3 and IRX5. Such discoveries suggest that associated non-coding variants can be embedded within or next to one gene, but commonly influence the expression of other, more distal effector genes. Advances in genetics and genomics are therefore contributing to a deeper understanding of childhood obesity, allowing for development of clinical tools and therapeutic agents.
肥胖是发达国家和发展中国家的一个主要健康负担。此外，儿童肥胖的发病率也在增加。肥胖通过增加 2 型糖尿病、心血管相关疾病和其他合并症的风险，大大增加了美国的死亡率。尽管过去几十年来环境发生了变化，包括高热量食物和久坐不动的生活方式增加，但肥胖风险的遗传易感性有非常明确的证据。儿童肥胖病例可以分为以下两种类型：综合征或非综合征。综合征性肥胖包括普拉德-威利综合征、Bardet-Biedl 综合征和 Alström 综合征等疾病。非综合征性肥胖病例可进一步分为罕见的单基因肥胖和更常见的多基因肥胖形式。全基因组关联研究（GWAS）和下一代测序的出现推动了我们对遗传因素导致儿童肥胖的理解取得了重大进展。许多罕见和常见的遗传变异已被证明有助于肥胖的遗传性，尽管这些变异的分子机制仍不清楚。GWAS 研究的一个重要警告是，它们并不严格代表基因靶点的发现，而只是发现了强有力的遗传信号。一个明显的例子是，在理解 FTO 基因内含子区域内关键肥胖信号方面取得了进展。事实证明，变异实际上所在的非编码区域实际上会影响 FTO 远端基因的表达，特别是 IRX3 和 IRX5。这些发现表明，相关的非编码变异可以嵌入或紧邻一个基因，但通常会影响其他更远端效应基因的表达。因此，遗传学和基因组学的进步有助于更深入地了解儿童肥胖，从而开发临床工具和治疗剂。
