GLP1R Gene Expression and Kidney Disease Progression
Authors: Triozzi Jefferson L. , Yu Zhihong , Giri Ayush , Chen Hua-Chang , Wilson Otis D. , Ferolito Brian , Ikizler T. Alp , Akwo Elvis A. , Robinson-Cohen Cassianne , Gaziano John Michael , Cho Kelly , Phillips Lawrence S. , Tao Ran , Pereira Alexandre C. , Hung Adriana M. ,   VA Million Veteran Program, Muralidhar Sumitra , Moser Jennifer , Deen Jennifer E. , Tsao Philip S. , Gaziano J. Michael , Hauser Elizabeth , Kilbourne Amy , Matheny Michael , Oslin Dave , Churby Lori , Whitbourne Stacey B. , Brewer Jessica V. , Shayan Shahpoor (Alex) , Selva Luis E. , Pyarajan Saiju , Cho Kelly , DuVall Scott L. , Brophy Mary T. , Stephens Brady , Connor Todd , Argyres Dean P. , Assimes Tim , Hung Adriana , Kranzler Henry , Aguayo Samuel , Ahuja Sunil , Alexander Kathrina , Androulakis Xiao M. , Balasubramanian Prakash , Ballas Zuhair , Beckham Jean , Bhushan Sujata , Boyko Edward , Cohen David , Dellitalia Louis , Faulk L. Christine , Fayad Joseph , Fujii Daryl , Gappy Saib , Gesek Frank , Greco Jennifer , Godschalk Michael , Gress Todd W. , Gupta Samir , Gutierrez Salvador , Harley John , Hamner Mark , Hurley Robin , Iruvanti Pran , Jacono Frank , Jhala Darshana , Kinlay Scott , Landry Michael , Liang Peter , Liangpunsakul Suthat , Lichy Jack , Mahan C. Scott , Marrache Ronnie , Mastorides Stephen , Mattocks Kristin , Meyer Paul , Moorman Jonathan , Morgan Timothy , Murdoch Maureen , Norton James , Okusaga Olaoluwa , Oursler Kris Ann , Poon Samuel , Rauchman Michael , Servatius Richard , Sharma Satish , Smith River , Sriram Peruvemba , Strollo Patrick , Tandon Neeraj , Villareal Gerardo , Walsh Jessica , Wells John , Whittle Jeffrey , Whooley Mary , Wilson Peter , Xu Junzhe , Yeh Shing Shing , Bast Elizabeth S. , Dryden Gerald Wayne , Hogan Daniel J. , Joshi Seema , Lo Tze Shien , Morales Providencia , Naik Eknath , Ong Michael K. , Petrakis Ismene , Rai Amneet S. , Yen Andrew W. 
Published: October 2024

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.