Mendelian Randomization Analysis of Genetic Proxies of Thiazide Diuretics and the Reduction of Kidney Stone Risk
Jefferson L. Triozzi, Ryan S. Hsi, Guanchao Wang, Elvis A. Akwo, Lee Wheless, Hua‐Chang Chen, Ran Tao, T. Alp İkizler, Cassianne Robinson‐Cohen, Adriana M. Hung, VA Million Veteran Program, Sumitra Muralidhar, Jennifer Moser, Jennifer E. Deen, Philip S. Tsao, J. Michael Gaziano, Elizabeth R. Hauser, Amy M. Kilbourne, Shiuh‐Wen Luoh, Michael E. Matheny, Dave Oslin, Lori Churby, Stacey B. Whitbourne, Jessica V. Brewer, Shahpoor Shayan, Luis E. Selva, Saiju Pyarajan, Kelly Cho, Scott L. DuVall, Mary T. Brophy, Brady Stephens, Todd Connor, Dean P. Argyres, Tim Assimes, Adriana M. Hung, Henry R. Kranzler, Samuel M. Aguayo, Sunil K. Ahuja, Kathrina Alexander, X. Michelle Androulakis, Prakash Balasubramanian, Zuhair K. Ballas, Jean C. Beckham, Sujata Bhushan, Edward J. Boyko, David Cohen, Louis J. Dell’Italia, L. Christine Faulk, Joseph Fayad, Daryl Fujii, Saib Gappy, F. A. Gesek, Jennifer Greco, Michael Godschalk, Todd Gress, Samir Gupta, Salvador Gutierrez, John B. Harley, Kimberly Hammer, Mark B. Hamner, Robin A. Hurley, Pran Iruvanti, Frank J. Jacono, Darshana Jhala, Scott Kinlay, Jon Klein, Michael Landry, Peter S. Liang, Suthat Liangpunsakul, Jack Lichy, Charles S. Mahan, Ronnie Marrache, Stephen Mastorides, Elisabeth Mates, Kristin Mattocks, Paul Meyer, Jonathan P. Moorman, Timothy R. Morgan, Maureen Murdoch, James Norton, Olaoluwa Okusaga, Kris Ann Oursler, Ana Palacio, Samuel Poon, Emily Potter, Michael Rauchman, Richard J. Servatius, Satish Sharma, River Smith, Peruvemba Sriram, Patrick Strollo, Neeraj Tandon, Gerardo Villareal, Agnes Wallbom, Jessica Walsh, John A. Wells, Jeff Whittle, Mary A. Whooley, Allison E. Williams, Peter W.F. Wilson
Abstract
Importance: Clinical trial data have called into question the efficacy of thiazide diuretics for the prevention of kidney stones. Objective: To identify whether there is an association between genetic proxies of thiazide diuretics and the risk of kidney stones. Design, Setting, and Participants: This genetic association study undertook a mendelian randomization analysis of derived exposures and outcomes from genome-wide association study summary statistics. Genetic proxies of thiazide diuretics were derived from the International Consortium for Blood Pressure. Kidney stone cases and controls were derived from the Million Veteran Program, UK Biobank, and the FinnGen study. These cross-sectional designs do not report a duration of follow-up. Data analysis was performed in May 2023. Exposure: Genetic proxies of thiazide diuretics were genetic variants in the thiazide-sensitive sodium chloride cotransporter gene associated with systolic blood pressure. Genetic proxies of β-blockers and systolic blood pressure served as negative controls. Main Outcomes and Measures: The main outcome was the odds of kidney stones. The secondary outcomes were serum laboratory values relevant to the treatment of kidney stones. Results: The main analysis included up to 1 079 657 individuals, including 50 832 kidney stone cases and 1 028 825 controls. In a meta-analysis of all cohorts, genetic proxies of thiazide diuretics were associated with a lower odds of kidney stones (OR, 0.85; 95% CI, 0.81-0.89; P < .001). Genetic proxies of β-blockers (OR, 1.02; 95% CI, 0.96-1.07; P = .52) and systolic blood pressure (OR, 1.00; 95% CI, 1.00-1.01; P = .49) were not associated with kidney stones. Genetic proxies of thiazide diuretics were associated with higher serum calcium (β [SE], 0.051 [0.0092]; P < .001) and total cholesterol (β [SE], 0.065 [0.015]; P < .001), but lower serum potassium (β [SE], -0.073 [0.022]; P < .001). Conclusions and Relevance: In this genetic association study, genetic proxies of thiazide diuretics were associated with reduced kidney stone risk. This finding reflects a drug effect over the course of a lifetime, unconstrained by the limited follow-up period of clinical trials.