Mendelian Randomization Analysis of Genetic Proxies of Thiazide Diuretics and the Reduction of Kidney Stone Risk
Authors: Triozzi Jefferson L. , Hsi Ryan S. , Wang Guanchao , Akwo Elvis A. , Wheless Lee , Chen Hua-Chang , Tao Ran , Ikizler T. Alp , Robinson-Cohen Cassianne , Hung Adriana M. ,   VA Million Veteran Program, Muralidhar Sumitra , Moser Jennifer , Deen Jennifer E. , Tsao Philip S. , Gaziano J. Michael , Hauser Elizabeth , Kilbourne Amy , Luoh Shiuh-Wen , 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 , Hammer Kimberly , Hamner Mark , Hurley Robin , Iruvanti Pran , Jacono Frank , Jhala Darshana , Kinlay Scott , Klein Jon , Landry Michael , Liang Peter , Liangpunsakul Suthat , Lichy Jack , Mahan C. Scott , Marrache Ronnie , Mastorides Stephen , Mates Elisabeth , Mattocks Kristin , Meyer Paul , Moorman Jonathan , Morgan Timothy , Murdoch Maureen , Norton James , Okusaga Olaoluwa , Oursler Kris Ann , Palacio Ana , Poon Samuel , Potter Emily , Rauchman Michael , Servatius Richard , Sharma Satish , Smith River , Sriram Peruvemba , Strollo Jr. Patrick , Tandon Neeraj , Villareal Gerardo , Wallbom Agnes , Walsh Jessica , Wells John , Whittle Jeffrey , Whooley Mary , Williams Allison E. , Wilson Peter , Xu Junzhe , Yeh Shing Shing 
Published: November 2023

ImportanceClinical trial data have called into question the efficacy of thiazide diuretics for the prevention of kidney stones.ObjectiveTo identify whether there is an association between genetic proxies of thiazide diuretics and the risk of kidney stones.Design, Setting, and ParticipantsThis 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.ExposureGenetic 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 MeasuresThe main outcome was the odds of kidney stones. The secondary outcomes were serum laboratory values relevant to the treatment of kidney stones.ResultsThe 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 &amp;lt; .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 &amp;lt; .001) and total cholesterol (β [SE], 0.065 [0.015]; P &amp;lt; .001), but lower serum potassium (β [SE], −0.073 [0.022]; P &amp;lt; .001).Conclusions and RelevanceIn 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.