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