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. 2024 Oct 1;7(10):e2440286.
doi: 10.1001/jamanetworkopen.2024.40286.

GLP1R Gene Expression and Kidney Disease Progression

Jefferson L Triozzi  1 , Zhihong Yu  2 , Ayush Giri  3   4 , Hua-Chang Chen  2 , Otis D Wilson  5 , Brian Ferolito  6 , T Alp Ikizler  1 , Elvis A Akwo  1 , Cassianne Robinson-Cohen  1 , John Michael Gaziano  6   7 , Kelly Cho  6   7 , Lawrence S Phillips  8   9 , Ran Tao  2   10 , Alexandre C Pereira  6   7 , Adriana M Hung  1   5 ; VA Million Veteran Program
Collaborators, Affiliations

GLP1R Gene Expression and Kidney Disease Progression

Jefferson L Triozzi et al. JAMA Netw Open. .

Abstract

Importance: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have nephroprotective properties beyond those related to weight loss and glycemic control.

Objective: To investigate the association of genetically proxied GLP-1RAs with kidney disease progression.

Design, setting, and participants: This genetic association study assembled a national retrospective cohort of veterans aged 18 years or older from the US Department of Veterans Affairs Million Veteran Program between January 10, 2011, and December 31, 2021. Data were analyzed from November 2023 to February 2024.

Exposures: Genetic risk score for systemic GLP1R gene expression that was calculated for each study participant based on genetic variants associated with GLP1R mRNA levels across all tissue samples within the Genotype-Tissue Expression project.

Main outcomes and measures: The primary composite outcome was incident end-stage kidney disease or a 40% decline in estimated glomerular filtration rate. Cox proportional hazards regression survival analysis assessed the association between genetically proxied GLP-1RAs and kidney disease progression.

Results: Among 353 153 individuals (92.5% men), median age was 66 years (IQR, 58.0-72.0 years) and median follow-up was 5.1 years (IQR, 3.1-7.2 years). Overall, 25.7% had diabetes, and 45.0% had obesity. A total of 4.6% experienced kidney disease progression. Overall, higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression in the unadjusted model (hazard ratio [HR], 0.96; 95% CI, 0.92-0.99; P = .02) and in the fully adjusted model accounting for baseline patient characteristics, body mass index, and the presence or absence of diabetes (HR, 0.96; 95% CI, 0.92-1.00; P = .04). The results were similar in sensitivity analyses stratified by diabetes or obesity status.

Conclusions and relevance: In this genetic association study, higher GLP1R gene expression was associated with a small reduction in risk of kidney disease progression. These findings support pleiotropic nephroprotective mechanisms of GLP-1RAs independent of their effects on body weight and glycemic control.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Triozzi reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Gaziano reported receiving grants from the US Department of Veterans Affairs (VA) during the conduct of the study. Dr Phillips reported receiving research grants from Eli Lilly and Company, GSK, Novartis, Merck, Novo Nordisk, Roche, AbbVie, Sanofi, Janssen, Pfizer, Kowa, and Boehringer Ingelheim to Emory University and/or the Foundation for Atlanta Veterans Education and Research (related to the Atlanta VA Healthcare System); serving as cofounder, president, secretary, chief medical and scientific officer, and a board member of Diasyst, Inc, and having equity and stock in Diasyst, Inc, outside the submitted work; and having a patent jointly held by Emory University and the VA for development of software aimed to help improve diabetes management, with an exclusive license to Diasyst, Inc. Dr Hung reported receiving a VA Clinical Science Research and Development (CSR&D) merit award to study “Genetics Of Chronic Kidney Disease and Hypertension-Risk Prediction and Drug Response in the Million Veteran Program (MVP);” serving as a gene-lifestyle interaction consultant for the National Heart, Lung, and Blood Institute; and receiving grants from Bayer to the Vanderbilt University Medical Center (VUMC), grants from Vertex to the VA for the AMPLITUD trial, and grants from Vertex to the VUMC during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart Demonstrating the Selection of Study Participants for the Survival Analysis
The national cohort was derived from the European Ancestry Veterans from the Million Veteran Program (MVP), release 4. ESKD indicates end-stage kidney disease; GLP-1RA, glucagon-like peptide 1 receptor agonist; GRS, genetic risk score.
Figure 2.
Figure 2.. Cumulative Hazard Plot for Kidney Disease Progression, Stratified by High vs Low Genetic Risk Score (GRS) for GLP1R Expression
Lower GLP1R expression represents the bottom tertile of GRS and higher expression, the top tertile. HR indicates hazard ratio.
Figure 3.
Figure 3.. Subgroup Survival Analyses for the Association of Genetic GLP1R Expression With Risk of Kidney Disease Progression
Analyses were adjusted for age, sex, 10 principal components of ancestry, baseline kidney function, use of an angiotensin-converting enzyme or angiotensin II receptor blocker, and blood pressure. The size of the data markers represents the sample size in each stratum.
See this image and copyright information in PMC

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