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<p>Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight loss. Between 6 and 12 months, GLP1-RA users had an average weight change of −3.93% or −6.00%, depending on the outcome definition, with modest ancestry-based differences. BS patients experienced −21.17% weight change between 6 and 48 months. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in <i>GLP1R</i>. A higher body mass index polygenic score was modestly linked to lower weight loss after BS (+0.7% per s.d., <i>P</i> = 1.24 × 10<sup>−4</sup>), but the effect attenuated in sensitivity analyses. Our findings suggest known genetic factors have limited impact on GLP1-RA effectiveness with respect to weight change and confirm treatment efficacy across ancestry groups.</p>

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Association between plausible genetic factors and weight loss from GLP1-RA and bariatric surgery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月18日

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  • Jakob German,
  • Mattia Cordioli,
  • Veronica Tozzo,
  • Sarah Urbut,
  • Kadri Arumäe,
  • Roelof A. J. Smit,
  • Jiwoo Lee,
  • Josephine H. Li,
  • Adrian Janucik,
  • Yi Ding,
  • Akintunde Akinkuolie,
  • Henrike O. Heyne,
  • Andrea Eoli,
  • Chadi Saad,
  • Yasser Al-Sarraj,
  • Rania Abdel-latif,
  • Shaban Mohammed,
  • Moza Al Hail,
  • Alexandra Barry,
  • Zhe Wang,
  • Tatiana Cajuso,
  • Andrea Corbetta,
  • Pradeep Natarajan,
  • Samuli Ripatti,
  • Anthony Philippakis,
  • Lukasz Szczerbinski,
  • Bogdan Pasaniuc,
  • Zoltán Kutalik,
  • Hamdi Mbarek,
  • Ruth J. F. Loos,
  • Uku Vainik,
  • Andrea Ganna

摘要

Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight loss. Between 6 and 12 months, GLP1-RA users had an average weight change of −3.93% or −6.00%, depending on the outcome definition, with modest ancestry-based differences. BS patients experienced −21.17% weight change between 6 and 48 months. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in GLP1R. A higher body mass index polygenic score was modestly linked to lower weight loss after BS (+0.7% per s.d., P = 1.24 × 10−4), but the effect attenuated in sensitivity analyses. Our findings suggest known genetic factors have limited impact on GLP1-RA effectiveness with respect to weight change and confirm treatment efficacy across ancestry groups.