基因建模的胰高血糖素样肽-1受体（GLP1R）和胃抑制多肽受体（GIPR）激动作用可减少暴饮暴食及与酒精相关的表型：一项多血统药物靶点孟德尔随机化研究

Genetically modeled GLP1R and GIPR agonism reduce binge drinking and alcohol-associated phenotypes: a multi-ancestry drug-target Mendelian randomization study.

作者信息

Reitz Joshua, Rosoff Daniel B, Perlstein Tyler, Wagner Alexandra, Jung Jeesun, Wagner Josephin, Reiner Benjamin C, Lohoff Falk W

机构信息

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

NIH Oxford-Cambridge Scholars Program, University of Oxford, Oxford, UK.

出版信息

Mol Psychiatry. 2025 Sep 10. doi: 10.1038/s41380-025-03199-3.

DOI:10.1038/s41380-025-03199-3

PMID:40931165

Abstract

Pharmacological modulation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) through dual GIP/GLP-1 receptor agonists, commonly used for diabetes and obesity, shows promise in reducing alcohol consumption. We applied drug-target Mendelian randomization (MR) using genetic variation at these loci to assess their long-term effects on problematic alcohol use (PAU), binge drinking, alcohol misuse classifications, liver health, and other substance use behaviors. Genetic proxies for lowered BMI, modeling the appetite-suppressing and weight-reducing effects of variants in both the GIPR and GLP1R loci ("GIPR/GLP1R"), were linked with reduced binge drinking in the primary (β = -0.44, 95% CI [-0.72, -0.15], P = 2.42 × 10) and replication data (β = -0.13, [-0.22, -0.04], P = 0.0058). HbA1c lowering via GIPR/GLP1R variants was associated with reduced risk of heavy drinking with psychiatric comorbidities versus low-risk drinking (odds ratio [OR] = 0.62, [0.45, 0.85], P = 0.0031), with replication in independent HbA1c data (OR = 0.71, [0.60, 0.84], P = 5.22 × 10) and directional consistency with reduced PAU. Analysis of individual loci indicated that both GIPR and GLP1R were protective against heavy drinking, underscoring the importance of both targets. While estimates for other substance use disorders (tobacco, cannabis, opioid) were consistently null, food preference analyses revealed that BMI lowering via GIPR/GLP1R reduced fatty food liking (β = -1.58, [-2.01, -1.14], P = 1.62 × 10) and increased vegetarian food liking (β = 2.08, [1.17, 2.99], P = 8.22 × 10), implicating metabolic and appetite regulation pathways for the alcohol consumption findings. For liver health, HbA1c lowering via GIPR/GLP1R was associated with reduced NAFLD (β = -0.34, [-0.50, -0.18], P = 2.74 × 10) and lower ALT levels (β = -0.26, [-0.38, -0.15], P = 8.39 × 10), with replication supporting these findings. Consistency across multiple MR methods and colocalization analyses strengthened causal inference. Mediation analysis suggested reductions in hazardous alcohol consumption partially explain the cardioprotective effects of these agonists. Multi-ancestry analyses supported directionally aligned relationships in non-European cohorts. These findings support further clinical exploration of GLP1R, GIPR, and dual agonists in addiction medicine.

摘要

通过双重GIP/GLP-1受体激动剂对胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）进行药理调节，常用于治疗糖尿病和肥胖症，在减少酒精消费方面显示出前景。我们利用这些基因座的基因变异应用药物靶点孟德尔随机化（MR）来评估它们对问题性饮酒（PAU）、暴饮、酒精滥用分类、肝脏健康和其他物质使用行为的长期影响。降低BMI的基因代理，模拟GIPR和GLP1R基因座中变异体的食欲抑制和体重减轻作用（“GIPR/GLP1R”），与原发性（β=-0.44，95%CI[-0.72，-0.15]，P=2.42×10）和复制数据（β=-0.13，[-0.22，-0.04]，P=0.0058）中暴饮的减少有关。通过GIPR/GLP1R变异体降低HbA1c与重度饮酒合并精神疾病的风险降低相关，与低风险饮酒相比（优势比[OR]=0.62，[0.45，0.85]，P=0.0031），在独立的HbA1c数据中得到复制（OR=0.71，[0.60，0.84]，P=5.22×10），并且与PAU减少具有方向一致性。对单个基因座的分析表明，GIPR和GLP1R都对重度饮酒有保护作用，强调了这两个靶点的重要性。虽然对其他物质使用障碍（烟草、大麻、阿片类药物）的估计始终为零，但食物偏好分析表明，通过GIPR/GLP1R降低BMI会降低对高脂肪食物的喜好（β=-1.58，[-2.01，-1.14]，P=1.62×10），并增加对素食的喜好（β=2.08，[1.17，2.99]，P=8.22×10），这暗示了酒精消费结果的代谢和食欲调节途径。对于肝脏健康，通过GIPR/GLP1R降低HbA1c与非酒精性脂肪性肝病（NAFLD）减少（β=-0.34，[-0.50，-0.18]，P=2.74×10）和较低的谷丙转氨酶（ALT）水平（β=-0.26，[-0.38，-0.15]，P=8.39×10）相关，复制结果支持了这些发现。多种MR方法和共定位分析的一致性加强了因果推断。中介分析表明，有害酒精消费的减少部分解释了这些激动剂的心脏保护作用。多血统分析支持非欧洲队列中方向一致的关系。这些发现支持在成瘾医学中对GLP1R、GIPR和双重激动剂进行进一步的临床探索。