PDF(Pubmed)
Abstract：
Pediatric obesity has steadily increased in recent decades. Large-scale genome-wide association studies (GWAS) conducted primarily in Eurocentric adult populations have identified approximately 100 loci that predispose to obesity and type II diabetes. GWAS in children and individuals of non-European descent, both disproportionately affected by obesity, are fewer. Rare syndromic and monogenic obesities account for only a small portion of childhood obesity, so understanding the role of other genetic variants and their combinations in heritable obesities is key to developing targeted and personalized therapies. Tight and responsive regulation of the cAMP-dependent protein kinase (PKA) signaling pathway is crucial to maintaining healthy energy metabolism, and mutations in PKA-linked genes represent the most common cause of monogenic obesity.
For this study, we performed targeted exome sequencing of 53 PKA signaling-related genes to identify variants in genomic DNA from a large, ethnically diverse cohort of obese or metabolically challenged youth.
We confirmed 49 high-frequency variants, including a novel variant in the PDE11A gene (c.152C>T). Several other variants were associated with metabolic characteristics within ethnic groups.
We conclude that a PKA pathway-specific variant search led to the identification of several new genetic associations with obesity in an ethnically diverse population.
For this study, we performed targeted exome sequencing of 53 PKA signaling-related genes to identify variants in genomic DNA from a large, ethnically diverse cohort of obese or metabolically challenged youth.
We confirmed 49 high-frequency variants, including a novel variant in the PDE11A gene (c.152C>T). Several other variants were associated with metabolic characteristics within ethnic groups.
We conclude that a PKA pathway-specific variant search led to the identification of several new genetic associations with obesity in an ethnically diverse population.
摘要：
■近几十年来，小儿肥胖症稳步增加。主要在以欧洲为中心的成人人群中进行的大规模全基因组关联研究（GWAS）已经确定了大约100个易患肥胖和II型糖尿病的基因座。非欧洲血统的儿童和个人的GWAS，两者都不成比例地受到肥胖的影响，少了。罕见的综合征和单基因肥胖仅占儿童肥胖的一小部分，因此，了解其他遗传变异及其组合在可遗传服从中的作用是开发靶向和个性化治疗的关键。cAMP依赖性蛋白激酶（PKA）信号通路的紧密和响应性调节对于维持健康的能量代谢至关重要，PKA相关基因的突变代表了单基因肥胖的最常见原因。
■对于这项研究，我们对53个PKA信号相关基因进行了靶向外显子组测序，以鉴定基因组DNA中的变异，肥胖或代谢困难的年轻人的种族多样化队列。
■我们确认了49个高频变种，包括PDE11A基因中的新变体(c.152C>T)。其他几种变异与种族群体的代谢特征有关。
■我们得出的结论是，PKA途径特异性变异搜索导致了在不同种族人群中与肥胖的几个新的遗传关联的鉴定。
■对于这项研究，我们对53个PKA信号相关基因进行了靶向外显子组测序，以鉴定基因组DNA中的变异，肥胖或代谢困难的年轻人的种族多样化队列。
■我们确认了49个高频变种，包括PDE11A基因中的新变体(c.152C>T)。其他几种变异与种族群体的代谢特征有关。
■我们得出的结论是，PKA途径特异性变异搜索导致了在不同种族人群中与肥胖的几个新的遗传关联的鉴定。
