基因模拟的GLP1R和GIPR激素减少过度饮酒和与酒精相关的表型:一个多祖先药物向的门德尔随机化研究
Joshua Reitz1, Daniel B Rosoff1,2, Tyler Perlstein1
1Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Molecular psychiatry
|September 10, 2025
概括
双GIP/GLP-1受体激动剂在减少酒精消耗和改善肝脏健康方面显示出有前途. 基因分析将GIPR和GLP1R位点的变异与减少过度饮酒和减少重度饮酒风险联系起来.
科学领域:
- 药理学和遗传学 药理学和遗传学
- 成 药物 药物 药物 药物
- 代谢障碍 代谢障碍 代谢障碍
背景情况:
- 双重葡萄糖类-1 (GLP-1) 和依赖葡萄糖的胰岛素托普多 (GIP) 受体激活剂用于糖尿病和肥胖症.
- 这些激动剂显示出降低酒精消费的潜力.
- 了解这些影响的遗传基础对于治疗开发至关重要.
研究的目的:
- 通过使用药物点孟德尔随机化 (MR) 来研究GIPR和GLP1R基位基因变异对问题性酒精使用 (PAU),过度饮酒和其他物质使用行为的长期影响.
- 评估这些变异对肝脏健康的影响,包括非酒精性脂肪性肝病 (NAFLD) 和氨酸转移酶 (ALT) 水平.
- 探索这些遗传变异,食物偏好和代谢调节之间的关系.
主要方法:
- 药物标孟德尔随机化 (MR) 分析,使用GIPR和GLP1R位置的遗传变异.
- 首次和复制分析与饮酒过度,PAU和重度饮酒的关联.
- 评估与肝脏健康标志物 (NAFLD,ALT) 和其他物质使用障碍的关联.
- 食物偏好分析和调解分析,以探索潜在的机制.
主要成果:
- 通过GIPR/GLP1R变异降低BMI的遗传代理与初级和复制数据中的大量饮酒量显著减少有关.
- 通过GIPR/GLP1R变体降低HbA1c与降低伴随精神疾病重度饮酒风险有关,并得到了复制的支持.
- 个别的GIPR和GLP1R位点显示出对重度饮酒的保护作用. 通过GIPR/GLP1R降低BMI,减少喜欢脂肪食物,增加喜欢素食食物.
- 通过GIPR/GLP1R降低HbA1c与减少NAFLD和降低ALT水平有关,并支持复制.
- 对于其他物质使用障碍 (烟草,大麻,阿片类药物) 没有发现一致的关联.
结论:
- 在GIPR和GLP1R位点中的遗传变异与减少问题性酒精使用,特别是狂饮和重度饮酒有关.
- 这些发现凸显了针对成医学中的GIPR和GLP1R通路的治疗潜力.
- 观察到的效果很可能通过食欲调节和代谢途径进行调节,也显示出对肝脏健康的好处.
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