Arshiya Mariam-Smith PhD, Joseph H. Breeyear PhD, Noah J. Daniels PhD, Kevin M. Pantalone DO, Marcio L. Griebeler MD, Alison A. Motsinger-Reif PhD, Daniel M. Rotroff PhD
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This study investigates the role of neurobeachin (<i>NBEA</i>), a gene that encodes a protein kinase A anchor protein, on weight loss response in two large, real-world cohorts.</p>\n </section>\n \n <section>\n \n <h3> Materials and Methods</h3>\n \n <p>We utilised data from individuals prescribed a GLP-1RA in the NIH All of Us (<i>N</i> = 6556) and validated in the UK Biobank (<i>N</i> = 241). The <i>NBEA</i> genetic score for weight loss (12–18 months) was developed using the NIH All of Us cohort and independently validated in the UK Biobank. Logistic regression modelled associations between the score and outcomes, including high responsiveness (top 20th percentile for weight loss) and non-responsiveness (weight change ≥0%).</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Individuals meeting the responsive <i>NBEA</i> score threshold were 82% more likely to be highly responsive (FDR <i>p</i> = 1·8 × 10<sup>−6</sup>) on liraglutide and were validated in the UK Biobank (odds ratio (OR) = 2·37; <i>p</i> = ·008). Individuals on semaglutide meeting this threshold for highly responsive had OR = 1·63 and OR = 2·21 in discovery and validation sets respectively (<i>p</i> < ·05). Individuals on liraglutide with a non-responsive <i>NBEA</i> score were 50% more likely to not lose weight (FDR <i>p</i> = 2.9 × 10<sup>−4</sup>) and were validated in the UK Biobank (OR = 1·81; <i>p</i> = ·041), but the non-response score did not validate for semaglutide.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>These findings indicate that <i>NBEA</i> genetic variation is predictive of GLP-1RA weight loss and may support future efforts to identify individuals likely to experience significant weight loss with GLP-1RAs, enabling personalised obesity treatment strategies.</p>\n </section>\n </div>","PeriodicalId":158,"journal":{"name":"Diabetes, Obesity & Metabolism","volume":"27 10","pages":"5632-5642"},"PeriodicalIF":5.7000,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://dom-pubs.onlinelibrary.wiley.com/doi/epdf/10.1111/dom.16612","citationCount":"0","resultStr":"{\"title\":\"Neurobeachin (NBEA) is a novel gene associated with GLP-1 receptor agonist associated weight loss\",\"authors\":\"Arshiya Mariam-Smith PhD, Joseph H. 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The <i>NBEA</i> genetic score for weight loss (12–18 months) was developed using the NIH All of Us cohort and independently validated in the UK Biobank. Logistic regression modelled associations between the score and outcomes, including high responsiveness (top 20th percentile for weight loss) and non-responsiveness (weight change ≥0%).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Individuals meeting the responsive <i>NBEA</i> score threshold were 82% more likely to be highly responsive (FDR <i>p</i> = 1·8 × 10<sup>−6</sup>) on liraglutide and were validated in the UK Biobank (odds ratio (OR) = 2·37; <i>p</i> = ·008). Individuals on semaglutide meeting this threshold for highly responsive had OR = 1·63 and OR = 2·21 in discovery and validation sets respectively (<i>p</i> < ·05). 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引用次数: 0
摘要
研究目的：美国近42%的成年人患有肥胖症，这是许多心脏代谢疾病和癌症的重要危险因素。胰高血糖素样肽-1受体激动剂（GLP-1RAs）是一种很有前景的减肥干预措施，但其疗效在个体之间差异很大。这项研究调查了神经沙滩素（NBEA）的作用，这是一种编码蛋白激酶a锚定蛋白的基因，在两个大型现实世界的队列中减肥反应。材料和方法：我们利用了在NIH All of Us （N = 6556）中开具GLP-1RA处方的个人数据，并在UK Biobank （N = 241）中进行了验证。体重减轻（12-18个月）的NBEA遗传评分是使用NIH All of Us队列开发的，并在英国生物银行独立验证。Logistic回归对评分和结果之间的关联进行建模，包括高反应性（体重减轻前20百分位）和无反应性（体重变化≥0%）。结果：满足反应性NBEA评分阈值的个体对利拉鲁肽高反应的可能性高出82% (FDR p = 1.8 × 10-6)，并在UK Biobank中得到验证(优势比(OR) = 2.37；p =·008)。在发现组和验证组中，使用semaglutide达到高反应阈值的个体的OR分别为1.63和2.21 (p -4)，并在UK Biobank中进行了验证(OR = 1.81；P =·041)，但未反应评分未验证西马鲁肽。结论：这些研究结果表明，NBEA遗传变异可预测GLP-1RA体重减轻，并可能支持未来识别GLP-1RAs可能显著减轻体重的个体，从而实现个性化的肥胖治疗策略。
Neurobeachin (NBEA) is a novel gene associated with GLP-1 receptor agonist associated weight loss
Aims
Nearly 42% of adults in the United States have obesity, a significant risk factor for many cardiometabolic diseases and cancers. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are promising interventions for weight loss, but their efficacy varies significantly across individuals. This study investigates the role of neurobeachin (NBEA), a gene that encodes a protein kinase A anchor protein, on weight loss response in two large, real-world cohorts.
Materials and Methods
We utilised data from individuals prescribed a GLP-1RA in the NIH All of Us (N = 6556) and validated in the UK Biobank (N = 241). The NBEA genetic score for weight loss (12–18 months) was developed using the NIH All of Us cohort and independently validated in the UK Biobank. Logistic regression modelled associations between the score and outcomes, including high responsiveness (top 20th percentile for weight loss) and non-responsiveness (weight change ≥0%).
Results
Individuals meeting the responsive NBEA score threshold were 82% more likely to be highly responsive (FDR p = 1·8 × 10−6) on liraglutide and were validated in the UK Biobank (odds ratio (OR) = 2·37; p = ·008). Individuals on semaglutide meeting this threshold for highly responsive had OR = 1·63 and OR = 2·21 in discovery and validation sets respectively (p < ·05). Individuals on liraglutide with a non-responsive NBEA score were 50% more likely to not lose weight (FDR p = 2.9 × 10−4) and were validated in the UK Biobank (OR = 1·81; p = ·041), but the non-response score did not validate for semaglutide.
Conclusion
These findings indicate that NBEA genetic variation is predictive of GLP-1RA weight loss and may support future efforts to identify individuals likely to experience significant weight loss with GLP-1RAs, enabling personalised obesity treatment strategies.
期刊介绍：
Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.
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