美国23andMe研究所Adam Auton小组研制了GLP1受体激动剂减重和副作用的遗传预测因子。该项研究成果发表在2026年4月8日出版的《自然》上。

为了研究这种变异的遗传基础，小组对27885名接受GLP1受体激动剂治疗的患者进行了一项自我报告的体重减轻和治疗相关副作用的全基因组关联研究。课题组研究人员在GLP1R中发现了一个错义变体，它与GLP1药物的疗效增加显著相关（P = 2.9 × 10^-10），每个效应等位基因拷贝预计可额外带来−0.76公斤的体重下降。

此外，该研究组发现GLP1R和GIPR的变异与GLP1药物相关的恶心或呕吐有关，而GIPR的关联仅限于使用替西肽的人。该研究团队将这些发现纳入更广泛的GLP1药物反应模型，并证明了根据疗效和副作用风险对患者进行分层的能力。这些发现提供了直接的遗传证据，表明药物靶基因的变异导致了人与人之间的反应差异，并为肥胖症治疗的精准医学方法奠定了基础。

研究人员表示，胰高血糖素样肽1 （GLP1）受体激动剂的开发，包括西马鲁肽和替西肽，已经改变了超重和肥胖的临床管理。然而，在减肥效果和副作用发生率方面，存在很大的人与人之间的差异。

附：英文原文

Title: Genetic predictors of GLP1 receptor agonist weight loss and side effects

Author: Su, Qiaojuan Jane, Ashenhurst, James R., Xu, Wanwan, Tran, Vinh, Ryanne Wu, R., Weldon, Catherine H., Shi, Jingchunzi, Hicks, Barry, Abul-Husn, Noura S., Aslibekyan, Stella, Holmes, Michael V., Koelsch, Bertram L., Auton, Adam

Issue&Volume: 2026-04-08

Abstract: The development of glucagon-like peptide 1 (GLP1) receptor agonists, including semaglutide and tirzepatide, has transformed the clinical management of overweight and obesity. However, substantial inter-person variability exists in both weight loss efficacy and the incidence of side effects1. To investigate the genetic basis of this variability, here we conduct a genome-wide association study of self-reported weight loss and treatment-related side effects in 27,885 people following GLP1 receptor agonist therapy. We identify a missense variant in GLP1R that is associated significantly with increased efficacy of GLP1 medications (P=2.9×1010), with an additional 0.76kg of weight loss expected per copy of the effect allele. Furthermore, we identify associations linking variation in both GLP1R and GIPR to GLP1 medication-related nausea or vomiting, with the GIPR association being restricted to people using tirzepatide. We incorporate these findings into a broader model of GLP1 medication response, and demonstrate the ability to stratify patients by efficacy and side effect risk. These findings provide direct genetic evidence that variation in the drug target genes contributes to inter-person variability in response and lay the foundation for precision medicine approaches in the treatment of obesity.

DOI: 10.1038/s41586-026-10330-z

Source: https://www.nature.com/articles/s41586-026-10330-z