Mariam-Smith Arshiya, Breeyear Joseph H, Daniels Noah J, Pantalone Kevin M, Griebeler Marcio L, Motsinger-Reif Alison A, Rotroff Daniel M
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Center for Quantitative Metabolic Research, Cleveland Clinic, Cleveland, Ohio, USA.
Diabetes Obes Metab. 2025 Oct;27(10):5632-5642. doi: 10.1111/dom.16612. Epub 2025 Jul 18.
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.
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%).
Individuals meeting the responsive NBEA score threshold were 82% more likely to be highly responsive (FDR p = 1·8 × 10) 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) and were validated in the UK Biobank (OR = 1·81; p = ·041), but the non-response score did not validate for semaglutide.
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.
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风险因素。胰高血糖素样肽-1受体激动剂（GLP-1RAs）是有前景的减肥干预措施，但其疗效在个体间差异显著。本研究调查了神经beachin（NBEA）基因（一种编码蛋白激酶A锚定蛋白的基因）在两个大型真实世界队列中对减肥反应的作用。
我们利用了美国国立卫生研究院“我们所有人”项目中开具GLP-1RA处方的个体数据（N = 6556），并在英国生物银行（N = 241）中进行了验证。使用美国国立卫生研究院“我们所有人”队列开发了减肥（12 - 18个月）的NBEA基因评分，并在英国生物银行中进行了独立验证。逻辑回归模型分析了该评分与结局之间的关联，包括高反应性（减肥排名前20%）和无反应性（体重变化≥0%）。
达到NBEA反应性评分阈值的个体使用利拉鲁肽时高反应性的可能性高82%（错误发现率p = 1.8×10），并在英国生物银行中得到验证（比值比（OR）= 2.37；p = 0.008）。司美格鲁肽达到该高反应性阈值的个体在发现集和验证集中的OR分别为1.63和2.21（p < 0.05）。利拉鲁肽治疗且NBEA评分无反应的个体体重未减轻的可能性高50%（错误发现率p = 2.9×10），并在英国生物银行中得到验证（OR = 1.81；p = 0.041），但无反应评分对司美格鲁肽未得到验证。
这些发现表明NBEA基因变异可预测GLP-1RA减肥效果，并可能支持未来识别可能通过GLP-1RAs实现显著体重减轻的个体的努力，从而实现个性化肥胖治疗策略。
