The Effects of GLUT9 and URAT1 Inhibitors on Cardiovascular Diseases: A Drug-Targeted Mendelian Randomization Study

The Effects of GLUT9 and URAT1 Inhibitors on Cardiovascular Diseases: A Drug-Targeted Mendelian Randomization Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effects of GLUT9 and URAT1 Inhibitors on Cardiovascular Diseases: A Drug-Targeted Mendelian Randomization Study Qian Xu, Xinyu Liang, Wei Shi, Huafeng Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6055930/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jun, 2025 Read the published version in International Urology and Nephrology → Version 1 posted You are reading this latest preprint version Abstract Objective The strong association between hyperuricemia and cardiovascular diseases prompts this study to investigate the effects of uric acid-lowering drugs, GLUT9 and URAT1 inhibitors (GLUT9i and URAT1i), on cardiovascular diseases using Mendelian randomization (MR) analyses. Methods In GWAS data, SNPs strongly associated with blood uric acid within 100kb regions around the GLUT9 and URAT1 genes are identified, serving as proxies for the targeted effects of genes on uric acid. Subsequently, these SNPs were utilized for MR analyses with gout, common cardiovascular diseases (heart failure, myocardial infarction, ischemic stroke, venous thromboembolism), and their risk factors (blood glucose, lipid levels, blood pressure). MR-Egger was employed for pleiotropy testing, and Cochran's Q test was utilized for heterogeneity testing to ensure the robustness of the MR analysis. Results Both URAT1i and GLUT9i are effective drugs for gout. URAT1i is associated with a reduced risk of heart failure (OR = 0.76, 95% CI 0.63, 0.92, P = 0.004), decreased diastolic blood pressure (β=-0.07, 95% CI -0.13, 0.00, P = 0.048), reduced high-density lipoprotein levels (β=-0.05, 95% CI -0.10, -0.01, P = 0.016), and increased fasting blood glucose levels (β = 0.07, 95% CI 0.02, 0.13, P = 0.006). Conversely, GLUT9i leads to reductions in fasting blood glucose (β =-0.03, 95% CI -0.05, -0.01, P = 0.013) and diastolic blood pressure (β =-0.03, 95% CI -0.05, -0.01, P = 0.005), and increases in high-density lipoprotein (β = 0.02, 95% CI 0.00, 0.03, P = 0.011) Conclusion For patients suffering from gout in conjunction with conditions like hyperglycemia, dyslipidemia, and hypertension, GLUT9i may represent a more promising therapeutic approach. Mendelian Randomization Drug Cardiovascular Diseases Hyperuricemia Gout Figures Figure 1 Figure 2 Figure 3 Introduction Gout is a musculoskeletal disorder caused by an imbalance in purine metabolism. Elevated serum uric acid levels are the most significant risk factor for the development of gout[ 1 , 2 ]. Patients with gout have a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors[ 3 , 4 ]. Meta-analyses and clinical studies have found that hyperuricemia is associated with an increased risk of hypertension, dyslipidemia, coronary artery disease, cerebrovascular accidents, and mortality from cardiovascular diseases[ 5 – 7 ]. URAT1 and GLUT9 are the primary regulators of uric acid transport in the kidneys[ 8 ]. URAT1, located on the apical membrane of human renal proximal tubule epithelial cells, plays a key role in uric acid reabsorption. URAT1 inhibitor (URAT1i) is considered a highly effective and promising class of uric acid-lowering drugs for the treatment of hyperuricemia, including probenecid, lesinurad, benzbromarone, and dotinurad[ 9 , 10 ]. GLUT9, previously known as a type II glucose/fructose transporter, is now recognized for its function as a high-capacity uric acid transporter expressed in the kidneys, liver, and several other tissues. Currently, there are no specific GLUT9 inhibitors (GLUT9i) available for clinical use. The effects of uric acid-lowering drugs on cardiovascular diseases show inconsistent results, necessitating further research[ 11 – 13 ]. Mendelian randomization (MR) studies aim to use genetic variations to assess the potential causal relationship between exposures and outcomes. MR design adheres to the Mendelian inheritance principle of "parental alleles being randomly allocated to offspring," utilizing genetic variations as instrumental variables to infer the association between phenotypes and diseases. Since the associations between genes and disease outcomes are not subject to common confounding factors such as postnatal environmental or behavioral factors, and the causal temporal order is logical, using genes as instrumental variables for disease association studies has become a hotspot in epidemiological research in recent years. Previous MR studies have explored the effects of lipid-lowering, antihypertensive, and antidiabetic medications on cardiovascular diseases[ 14 – 16 ]. However, the impact of uric acid-lowering drugs on cardiovascular diseases has not yet been studied. Because mutations in the GLUT9, URAT1 gene reduce uric acid levels, and uric acid is associated with cardiovascular disease, it is hypothesized that GLUT9i, URAT1i reduce the risk of cardiovascular disease by lowering uric acid levels. Therefore, this study employs the MR method to investigate the effects of URAT1i and GLUT9i on cardiovascular diseases and their risk factors. Methods Data Sources High-quality Genome-Wide Association Studies (GWAS) on uric acid, gout, cardiovascular diseases (heart failure, ischemic stroke, myocardial infarction, venous thromboembolism), and cardiovascular risk factors (fasting blood glucose, systolic blood pressure, diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, total cholesterol) were searched on PubMed, focusing on recent years. These studies were selected for having a large number of participants and numerous SNPs. The diagnostic criteria of the disease can be seen in the original text. The GWAS data for serum uric acid originated from a meta-analysis based on a European population (n = 288,649) conducted by the CKDGen Consortium in 2021[ 17 ]. This meta-analysis did not include data from the UK Biobank, and there was no significant sample overlap with the GWAS data for the outcomes. There was no significant heterogeneity in this meta-analysis. The data for venous thromboembolism were sourced from FINN. All GWAS included European populations. The GWAS data for uric acid and outcomes are detailed in Supplementary Table 1[ 18 – 23 ]. SNP Selection SNPs consistent with the three assumptions of MR (relevance, independence and exclusion restriction) were screened from the uric acid GWAS data to represent the uric acid-lowering effect of URAT1i and GLUT9i. SNPs strongly associated with the exposure were selected based on conditions of P 0.01. Linkage disequilibrium was addressed by removing SNPs with R 2 < 0.3. The chromosomal locations for GLUT9 and URAT1 were referenced from NCBI, being 4:9827848–10041894 and 11:64358692–64369816, respectively. SNPs significantly associated with the genes were screened within a range of ± 100kb of the chromosomal positions. SNP phenotypes were checked on the PhenoScanner platform, and SNPs related to cardiovascular diseases or directly related to gout were removed to ensure the SNPs did not directly affect the cardiovascular system or affect it through gout (only through influencing serum uric acid levels). Ultimately, 7 SNPs for URAT1i and 23 SNPs for GLUT9i were identified. The F values (F=(β/SE) 2 ) for these SNPs were all greater than 10 (Supplementary Table 2). Research Procedure First step, MR analyses will be performed using SNPs of URAT1 and GLUT9 separately to investigate their associations with gout and common cardiovascular diseases (heart failure, ischemic stroke, myocardial infarction, venous thromboembolism). Second step, MR analyses will be conducted again using fasting blood glucose, systolic blood pressure, diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, and total cholesterol as outcomes to explore the effects of SNPs of URAT1 and GLUT9 on these biomarkers. The flowchart is shown in Fig. 1 . Statistics This study primarily employed the inverse variance weighted (IVW) method, which involves regression without the inclusion of an intercept term, and uses the inverse of the outcome variance as the weighting factor. Additionally, MR-Egger regression and the Weighted Median approach were utilized to augment the primary results. The MR-PRESSO method was employed to identify outliers. In instances where outliers were detected, they were excluded, and the analysis was re-conducted. Heterogeneity among the studies was assessed using Cochran's Q statistic. To address potential horizontal pleiotropy in this MR analysis, the MR-Egger intercept test was conducted. A statistically significant intercept term in the MR-Egger intercept analysis indicates substantial horizontal pleiotropy. P-value of less than 0.05 was considered statistically significant. All statistical analyses were carried out using R version 4.3.2, employing packages such as TwoSampleMR, and MR-PRESSO. We have adhered to the STROBE-MR guidelines and have included the STROBE-MR checklist. Results The impact of URAT1i and GLUT9i on cardiovascular diseases. IVW results demonstrate that genetic substitutions of URAT1i and GLUT9i both reduce the risk of gout, validating the reliability of the selected SNPs. URAT1i significantly reduced the risk of heart failure (IVW: OR = 0.89, 95%CI 0.83, 0.97, P = 0.004). While GLUT9 inhibition also showed a trend towards risk reduction, it was not statistically significant (IVW: OR = 0.92, 95%CI 0.85, 1.01, P = 0.066). URAT1i and GLUT9i did not show significant effects on the risk of myocardial infarction, venous thromboembolism, or ischemic stroke (Fig. 2 ). Detailed MR analysis results are provided in Supplementary Tables 3. The MR analysis indicated no significant pleiotropy or heterogeneity (Supplementary Table 3). The effects of URAT1i and GLUT9i on cardiovascular risk factors. URAT1i may potentially reduce systolic blood pressure (β=-0.07, 95% CI -0.13, 0.00, P = 0.048) and high-density lipoprotein (β=-0.05, 95% CI -0.10, -0.01, P = 0.016), while increasing fasting blood glucose (β = 0.07, 95% CI 0.02, 0.13, P = 0.006). Glut9i appears to lower blood glucose (β=-0.03, 95% CI -0.05, -0.01, P = 0.013), decrease diastolic blood pressure (β=-0.03, 95% CI -0.05, -0.01, P = 0.005), and increase high-density lipoprotein (β = 0.02, 95% CI 0.00, 0.03, P = 0.011) (Fig. 3 ). Detailed MR analysis results can be found in Supplementary Tables 4. The MR analysis reveals no apparent pleiotropy or heterogeneity (Supplementary Table 4). Discussion The results suggest that URAT1i reduces the risk of heart failure, lowers systolic blood pressure, decreases high-density lipoprotein levels, and increases fasting blood glucose. Additionally, GLUT9i is associated with decreased fasting blood glucose, decreased diastolic blood pressure, and increased high-density lipoprotein levels. These findings are consistent with another MR analysis indicating that uric acid-lowering therapy may provide cardiovascular benefits in preventing heart failure[ 24 ]. Compared to patients without hyperuricemia or gout, those with hyperuricemia or gout are more likely to develop heart failure[ 25 ]. Benzbromarone (a URAT1i) has shown significant improvement in diastolic dysfunction in comparison to the control group[ 26 ]. Dotinurad, as a highly selective URAT1i, has been marketed in Japan. Treatment with dotinurad for 24 weeks has been beneficial in impacting arterial stiffness and oxidative stress, leading to blood pressure reduction[ 10 , 27 ]. Dotinurad significantly attenuates high-fat diet-induced cardiac fibrosis, inflammatory response, and cardiac dysfunction. It may represent a promising therapeutic candidate for heart failure[ 28 ]. In the renal tubules, GLUT9 transports uric acid at a rate 45–60 times faster than glucose, and it has been demonstrated that GLUT9-mediated uric acid transport is enhanced by glucose and, to a lesser extent, by fructose[ 29 ]. The MR results from this study also GLUT9i can lower blood glucose levels, corroborating previous research findings. A prior MR analysis regarding GLUT9 gene variants suggested that a reduction in serum uric acid has a causal effect in lowering blood pressure[ 30 ]. While the precise pathways linking serum uric acid to elevated blood pressure have not been fully elucidated, previous studies have proposed several potential mechanisms. These include renal vascular constriction due to microvascular diseases, impaired endothelial function or compliance, and disturbances in sodium and volume homeostasis[ 31 , 32 ]. In mouse models specifically engineered with a kidney-specific knockout of GLUT9, a slight decrease was observed in both diastolic and systolic blood pressure. Furthermore, in liver-specific GLUT9 knockout mice, there was an improvement in Metabolic associated fatty liver disease and suppression of hepatic expression of key genes involved in lipogenesis[ 33 , 34 ]. However, the impact of GLUT9 inhibition on high-density lipoprotein levels still lacks comprehensive research and needs further investigation. Compared to observational studies, this study has clear advantages. MR analysis, utilizing genetic information as a tool for causal inference studies, can yield statistically convincing results. This method allows clinicians to sidestep the complexities and high costs associated with randomized clinical trials and alleviates common ethical concerns in clinical settings. However, this study also presents several limitations: The drug-MR approach cannot fully emulate the real-life pharmacodynamics of a drug. The analysis was centered on the impact of the drug through uric acid reduction, disregarding other possible mechanisms of the drug's action. Additionally, the side effects stemming from the drug's metabolism could not be evaluated. The study exclusively involved European populations and did not stratify by gender. Hence, the findings might not be universally applicable to other ethnic groups or specific to one gender. Similar to other MR analyses, the reliability of the results could be compromised by the unknown pleiotropy of SNPs. These limitations highlight the necessity for a cautious interpretation of the findings and suggest areas for future research to explore and validate the outcomes further. Conclusion Both URAT1i and GLUT9i are effective treatments for gout, and GLUT9i has the added benefits of lowering fasting glucose, reducing diastolic blood pressure, and increasing high-density lipoprotein levels. For patients suffering from gout in conjunction with conditions like hyperglycemia, dyslipidemia, and hypertension, GLUT9i may represent a more promising therapeutic approach. Statements and Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials Urate's GWAS data is available at CKDGEN: http://ckdgen.imbi.uni-freiburg.de. Blood lipid of GWAS from http://csg.sph.umich.edu/willer/public/glgc-lipids2021. Other GWAS data can be accessed at the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk) for the following conditions and factors. Gout: ebi-a-GCST90038687, Heart Failure: ebi-a-GCST009541, Myocardial Infarction: ebi-a-GCST90018877, Ischemic Stroke: ebi-a-GCST90018864, Venous Thromboembolism: finn-b-I9_VTE, Fasting Glucose: ebi-a-GCST90002232, Systolic Blood Pressure: ebi-a-GCST90029011, Diastolic Blood Pressure: ebi-a-GCST90029010. Competing interests The authors declare that they have no competing interests. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by funding from the Natural Science Foundation of Tianjin (No. 23JCYBJC00700). Authors' contributions The manuscript has been read and approved by all of the authors. Qian Xu: Data curation, Writing-Original draft preparation. Xinyu Liang and Wei Shi: Visualization. Huafeng Zhang Writing-Guiding and Reviewing. Acknowledgements We extend our sincere gratitude to the researchers who have shared their GWAS data, making this study possible, and we extend our gratitude to the FINN database for their support and contribution. References Richette P, Bardin T: Gout . Lancet 2010, 375 (9711):318-328. Dalbeth N, Merriman TR, Stamp LK: Gout . Lancet 2016, 388 (10055):2039-2052. Choi HK, Curhan G: Independent impact of gout on mortality and risk for coronary heart disease . Circulation 2007, 116 (8):894-900. De Vera MA, Rahman MM, Bhole V, Kopec JA, Choi HK: Independent impact of gout on the risk of acute myocardial infarction among elderly women: a population-based study . Ann Rheum Dis 2010, 69 (6):1162-1164. Gupta MK, Singh JA: Cardiovascular Disease in Gout and the Protective Effect of Treatments Including Urate-Lowering Therapy . Drugs 2019, 79 (5):531-541. Bardin T, Richette P: Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options . BMC Med 2017, 15 (1):123. Cipolletta E, Tata LJ, Nakafero G, Avery AJ, Mamas MA, Abhishek A: Association Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout . JAMA 2022, 328 (5):440-450. Dalbeth N, Gosling AL, Gaffo A, Abhishek A: Gout . Lancet 2021, 397 (10287):1843-1855. Hoy SM: Lesinurad: First Global Approval . Drugs 2016, 76 (4):509-516. Tanaka A, Taguchi I, Hisauchi I, Yoshida H, Shimabukuro M, Hongo H, Ishikawa T, Kadokami T, Yagi S, Sata M et al : Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA) . Eur J Med Res 2023, 28 (1):238. Sawada S, Kajiyama K, Shida H, Kimura R, Nakazato Y, Iguchi T, Oniyama Y, Ishiguro C, Uyama Y: Cardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan . Clin Transl Sci 2023, 16 (2):206-215. Lin HC, Daimon M, Wang CH, Ho Y, Uang YS, Chiang SJ, Wang LH: Allopurinol, benzbromarone and risk of coronary heart disease in gout patients: A population-based study . Int J Cardiol 2017, 233 :85-90. Chen JH, Lan JL, Cheng CF, Liang WM, Lin HY, Tsay GJ, Yeh WT, Pan WH: Effect of Urate-lowering Therapy on the Risk of Cardiovascular Disease and All-cause Mortality in Patients with Gout: A Case-matched Cohort Study . J Rheumatol 2015, 42 (9):1694-1701. Cupido AJ, Reeskamp LF, Hingorani AD, Finan C, Asselbergs FW, Hovingh GK, Schmidt AF: Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study . JAMA Cardiol 2022, 7 (9):955-964. Wang M, Zhang Z, Georgakis MK, Karhunen V, Liu D: The Impact of Genetically Proxied AMPK Activation, the Target of Metformin, on Functional Outcome Following Ischemic Stroke . J Stroke 2023, 25 (2):266-271. Li Y, Xiao W, Huang N, Zhuang Z, Zhang L, Wang W, Song Z, Zhao Y, Dong X, Xu M et al : The effects of blood pressure and antihypertensive drugs on heart failure: A Mendelian randomization study . Nutr Metab Cardiovasc Dis 2023, 33 (7):1420-1428. Tin A, Marten J, Halperin Kuhns VL, Li Y, Wuttke M, Kirsten H, Sieber KB, Qiu C, Gorski M, Yu Z et al : Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels . Nat Genet 2019, 51 (10):1459-1474. Donertas HM, Fabian DK, Valenzuela MF, Partridge L, Thornton JM: Common genetic associations between age-related diseases . Nat Aging 2021, 1 (4):400-412. Shah S, Henry A, Roselli C, Lin H, Sveinbjornsson G, Fatemifar G, Hedman AK, Wilk JB, Morley MP, Chaffin MD et al : Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure . Nat Commun 2020, 11 (1):163. Sakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, Narita A, Konuma T, Yamamoto K, Akiyama M et al : A cross-population atlas of genetic associations for 220 human phenotypes . Nat Genet 2021, 53 (10):1415-1424. Chen J, Spracklen CN, Marenne G, Varshney A, Corbin LJ, Luan J, Willems SM, Wu Y, Zhang X, Horikoshi M et al : The trans-ancestral genomic architecture of glycemic traits . Nat Genet 2021, 53 (6):840-860. Loh PR, Kichaev G, Gazal S, Schoech AP, Price AL: Mixed-model association for biobank-scale datasets . Nat Genet 2018, 50 (7):906-908. Graham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW et al : The power of genetic diversity in genome-wide association studies of lipids . Nature 2021, 600 (7890):675-679. Yang F, Hu T, Cui H: Serum urate and heart failure: a bidirectional Mendelian randomization study . Eur J Prev Cardiol 2022, 29 (11):1570-1578. Han Y, Cao Y, Han X, Di H, Yin Y, Wu J, Zhang Y, Zeng X: Hyperuricemia and gout increased the risk of long-term mortality in patients with heart failure: insights from the National Health and Nutrition Examination Survey . J Transl Med 2023, 21 (1):463. Ke J, Pan J, Lin H, Han Z, Gu J: Uric acid-lowering therapy with benzbromarone in hypertension with asymptomatic hyperuricemia: a randomized study focusing left ventricular diastolic function . Curr Med Res Opin 2023, 39 (7):947-953. Yanai H, Katsuyama H, Hakoshima M, Adachi H: Urate Transporter 1 Can Be a Therapeutic Target Molecule for Chronic Kidney Disease and Diabetic Kidney Disease: A Retrospective Longitudinal Study . Biomedicines 2023, 11 (2). Tanaka Y, Nagoshi T, Takahashi H, Oi Y, Yasutake R, Yoshii A, Kimura H, Kashiwagi Y, Tanaka TD, Shimoda M et al : URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease . iScience 2023, 26 (9):107730. Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, Doblado M, Evans S, Eyheramendy S, Onipinla A, Howard P et al : SLC2A9 is a high-capacity urate transporter in humans . PLoS Med 2008, 5 (10):e197. Parsa A, Brown E, Weir MR, Fink JC, Shuldiner AR, Mitchell BD, McArdle PF: Genotype-based changes in serum uric acid affect blood pressure . Kidney Int 2012, 81 (5):502-507. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ: Hyperuricemia induces endothelial dysfunction . Kidney Int 2005, 67 (5):1739-1742. Maxwell AJ, Bruinsma KA: Uric acid is closely linked to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease . J Am Coll Cardiol 2001, 38 (7):1850-1858. Zeng H, Tang C, Lin B, Yu M, Wang X, Wang J, Chen S, Yu C: The regulation effect of GLUT9/SLC2A9 on intrahepatic uric acid level and metabolic associated fatty liver disease . Hepatol Int 2022, 16 (5):1064-1074. Auberson M, Stadelmann S, Stoudmann C, Seuwen K, Koesters R, Thorens B, Bonny O: SLC2A9 (GLUT9) mediates urate reabsorption in the mouse kidney . Pflugers Arch 2018, 470 (12):1739-1751. Additional Declarations No competing interests reported. Supplementary Files 11.xlsx Cite Share Download PDF Status: Published Journal Publication published 06 Jun, 2025 Read the published version in International Urology and Nephrology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6055930","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":418279698,"identity":"04d75405-e45f-40ef-933c-e8984ea5cea2","order_by":0,"name":"Qian Xu","email":"","orcid":"","institution":"Tianjin University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Xu","suffix":""},{"id":418279701,"identity":"61d129f7-eee9-4409-bc3a-0739540f4647","order_by":1,"name":"Xinyu Liang","email":"","orcid":"","institution":"Tianjin Medical University General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xinyu","middleName":"","lastName":"Liang","suffix":""},{"id":418279702,"identity":"c168bc4a-4b14-4b8c-921d-fe8a08500d0e","order_by":2,"name":"Wei Shi","email":"","orcid":"","institution":"Tianjin Medical University General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Shi","suffix":""},{"id":418279703,"identity":"f0766a14-6850-400b-b658-a66edc4f4635","order_by":3,"name":"Huafeng Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYDACZoYEBsYGBgb7ZuaDDxIqagjr4IFpMWBnSzZ4cOYYEVpABFgLP4+a5MMWZsJa7NkZnm7m3XFY3pyZh60isYGNgb+9O4GQw9Ju8545bLizmffYjcQdMgwSZ85uIEJL22HGhsN8aTcSz7AxGEjkEqfFvuEwj1lBYhsz8VoSNwC1MBCn5TBD2s25benJM5vZkiUSzhzjIegX9v4zaTfetlnb9vMfPvjxR0WNHH97L34tQHsSULkElIPtOUCEolEwCkbBKBjRAACwqEhOgZ+BKwAAAABJRU5ErkJggg==","orcid":"","institution":"Tianjin Medical University General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Huafeng","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-02-18 11:53:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6055930/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6055930/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11255-025-04594-z","type":"published","date":"2025-06-06T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":76880777,"identity":"6cbc478a-db40-4428-b075-ef845516174e","added_by":"auto","created_at":"2025-02-21 17:05:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":611806,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic diagram for analysis.\u003c/p\u003e","description":"","filename":"F1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6055930/v1/6a4c16a085be851a390979bc.jpg"},{"id":76880782,"identity":"bdfd9468-c7e6-4fc3-91f7-b503d4d16298","added_by":"auto","created_at":"2025-02-21 17:05:32","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":346046,"visible":true,"origin":"","legend":"\u003cp\u003eMR analysis results (IVW) of URAT1i and GLUT9i on gout and cardiovascular diseases. URAT1i: URAT1 inhibitor, GLUT9i: GLUT9 inhibitor.\u003c/p\u003e","description":"","filename":"F2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6055930/v1/863664ed9d0b04b81db7dd32.jpg"},{"id":76880322,"identity":"7bd5cbe3-621a-4c97-a56e-00bd9ca1f2e0","added_by":"auto","created_at":"2025-02-21 16:57:32","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":411285,"visible":true,"origin":"","legend":"\u003cp\u003eMR analysis results (IVW) of URAT1i and GLUT9i on risk factors for cardiovascular diseases. URAT1i: URAT1 inhibitor, GLUT9i: GLUT9 inhibitor.\u003c/p\u003e","description":"","filename":"F3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6055930/v1/9a18b689b97edb7bf26b5c33.jpg"},{"id":84242518,"identity":"84cf17f3-1449-4c21-b222-0cc73e76033c","added_by":"auto","created_at":"2025-06-09 16:08:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3048172,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6055930/v1/bcc47046-9bd1-44e2-9303-c0171da78046.pdf"},{"id":76880776,"identity":"93bfe9b9-e456-4a15-b94b-1861dff04b0b","added_by":"auto","created_at":"2025-02-21 17:05:32","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":28315,"visible":true,"origin":"","legend":"","description":"","filename":"11.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6055930/v1/6503a2d9cac46b1ce567df61.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effects of GLUT9 and URAT1 Inhibitors on Cardiovascular Diseases: A Drug-Targeted Mendelian Randomization Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGout is a musculoskeletal disorder caused by an imbalance in purine metabolism. Elevated serum uric acid levels are the most significant risk factor for the development of gout[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Patients with gout have a higher incidence of cardiovascular diseases, independent of traditional cardiovascular risk factors[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Meta-analyses and clinical studies have found that hyperuricemia is associated with an increased risk of hypertension, dyslipidemia, coronary artery disease, cerebrovascular accidents, and mortality from cardiovascular diseases[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eURAT1 and GLUT9 are the primary regulators of uric acid transport in the kidneys[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. URAT1, located on the apical membrane of human renal proximal tubule epithelial cells, plays a key role in uric acid reabsorption. URAT1 inhibitor (URAT1i) is considered a highly effective and promising class of uric acid-lowering drugs for the treatment of hyperuricemia, including probenecid, lesinurad, benzbromarone, and dotinurad[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. GLUT9, previously known as a type II glucose/fructose transporter, is now recognized for its function as a high-capacity uric acid transporter expressed in the kidneys, liver, and several other tissues. Currently, there are no specific GLUT9 inhibitors (GLUT9i) available for clinical use. The effects of uric acid-lowering drugs on cardiovascular diseases show inconsistent results, necessitating further research[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMendelian randomization (MR) studies aim to use genetic variations to assess the potential causal relationship between exposures and outcomes. MR design adheres to the Mendelian inheritance principle of \"parental alleles being randomly allocated to offspring,\" utilizing genetic variations as instrumental variables to infer the association between phenotypes and diseases. Since the associations between genes and disease outcomes are not subject to common confounding factors such as postnatal environmental or behavioral factors, and the causal temporal order is logical, using genes as instrumental variables for disease association studies has become a hotspot in epidemiological research in recent years. Previous MR studies have explored the effects of lipid-lowering, antihypertensive, and antidiabetic medications on cardiovascular diseases[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, the impact of uric acid-lowering drugs on cardiovascular diseases has not yet been studied. Because mutations in the GLUT9, URAT1 gene reduce uric acid levels, and uric acid is associated with cardiovascular disease, it is hypothesized that GLUT9i, URAT1i reduce the risk of cardiovascular disease by lowering uric acid levels. Therefore, this study employs the MR method to investigate the effects of URAT1i and GLUT9i on cardiovascular diseases and their risk factors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eData Sources\u003c/p\u003e\n\u003cp\u003eHigh-quality Genome-Wide Association Studies (GWAS) on uric acid, gout, cardiovascular diseases (heart failure, ischemic stroke, myocardial infarction, venous thromboembolism), and cardiovascular risk factors (fasting blood glucose, systolic blood pressure, diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, total cholesterol) were searched on PubMed, focusing on recent years. These studies were selected for having a large number of participants and numerous SNPs. The diagnostic criteria of the disease can be seen in the original text. The GWAS data for serum uric acid originated from a meta-analysis based on a European population (n\u0026thinsp;=\u0026thinsp;288,649) conducted by the CKDGen Consortium in 2021[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. This meta-analysis did not include data from the UK Biobank, and there was no significant sample overlap with the GWAS data for the outcomes. There was no significant heterogeneity in this meta-analysis. The data for venous thromboembolism were sourced from FINN. All GWAS included European populations. The GWAS data for uric acid and outcomes are detailed in Supplementary Table\u0026nbsp;1[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eSNP Selection\u003c/p\u003e\n\u003cp\u003eSNPs consistent with the three assumptions of MR (relevance, independence and exclusion restriction) were screened from the uric acid GWAS data to represent the uric acid-lowering effect of URAT1i and GLUT9i. SNPs strongly associated with the exposure were selected based on conditions of P\u0026thinsp;\u0026lt;\u0026thinsp;5E-8 and MAF\u0026thinsp;\u0026gt;\u0026thinsp;0.01. Linkage disequilibrium was addressed by removing SNPs with R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.3. The chromosomal locations for GLUT9 and URAT1 were referenced from NCBI, being 4:9827848\u0026ndash;10041894 and 11:64358692\u0026ndash;64369816, respectively. SNPs significantly associated with the genes were screened within a range of \u0026plusmn;\u0026thinsp;100kb of the chromosomal positions. SNP phenotypes were checked on the PhenoScanner platform, and SNPs related to cardiovascular diseases or directly related to gout were removed to ensure the SNPs did not directly affect the cardiovascular system or affect it through gout (only through influencing serum uric acid levels). Ultimately, 7 SNPs for URAT1i and 23 SNPs for GLUT9i were identified. The F values (F=(\u0026beta;/SE)\u003csup\u003e2\u003c/sup\u003e) for these SNPs were all greater than 10 (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\n\u003cp\u003eResearch Procedure\u003c/p\u003e\n\u003cp\u003eFirst step, MR analyses will be performed using SNPs of URAT1 and GLUT9 separately to investigate their associations with gout and common cardiovascular diseases (heart failure, ischemic stroke, myocardial infarction, venous thromboembolism). Second step, MR analyses will be conducted again using fasting blood glucose, systolic blood pressure, diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, and total cholesterol as outcomes to explore the effects of SNPs of URAT1 and GLUT9 on these biomarkers. The flowchart is shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cp\u003eStatistics\u003c/p\u003e\n\u003cp\u003eThis study primarily employed the inverse variance weighted (IVW) method, which involves regression without the inclusion of an intercept term, and uses the inverse of the outcome variance as the weighting factor. Additionally, MR-Egger regression and the Weighted Median approach were utilized to augment the primary results. The MR-PRESSO method was employed to identify outliers. In instances where outliers were detected, they were excluded, and the analysis was re-conducted. Heterogeneity among the studies was assessed using Cochran\u0026apos;s Q statistic. To address potential horizontal pleiotropy in this MR analysis, the MR-Egger intercept test was conducted. A statistically significant intercept term in the MR-Egger intercept analysis indicates substantial horizontal pleiotropy.\u003c/p\u003e\n\u003cp\u003eP-value of less than 0.05 was considered statistically significant. All statistical analyses were carried out using R version 4.3.2, employing packages such as TwoSampleMR, and MR-PRESSO.\u003c/p\u003e\n\u003cp\u003eWe have adhered to the STROBE-MR guidelines and have included the STROBE-MR checklist.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe impact of URAT1i and GLUT9i on cardiovascular diseases.\u003c/p\u003e \u003cp\u003eIVW results demonstrate that genetic substitutions of URAT1i and GLUT9i both reduce the risk of gout, validating the reliability of the selected SNPs. URAT1i significantly reduced the risk of heart failure (IVW: OR\u0026thinsp;=\u0026thinsp;0.89, 95%CI 0.83, 0.97, P\u0026thinsp;=\u0026thinsp;0.004). While GLUT9 inhibition also showed a trend towards risk reduction, it was not statistically significant (IVW: OR\u0026thinsp;=\u0026thinsp;0.92, 95%CI 0.85, 1.01, P\u0026thinsp;=\u0026thinsp;0.066). URAT1i and GLUT9i did not show significant effects on the risk of myocardial infarction, venous thromboembolism, or ischemic stroke (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Detailed MR analysis results are provided in Supplementary Tables\u0026nbsp;3. The MR analysis indicated no significant pleiotropy or heterogeneity (Supplementary Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe effects of URAT1i and GLUT9i on cardiovascular risk factors.\u003c/p\u003e \u003cp\u003eURAT1i may potentially reduce systolic blood pressure (β=-0.07, 95% CI -0.13, 0.00, P\u0026thinsp;=\u0026thinsp;0.048) and high-density lipoprotein (β=-0.05, 95% CI -0.10, -0.01, P\u0026thinsp;=\u0026thinsp;0.016), while increasing fasting blood glucose (β\u0026thinsp;=\u0026thinsp;0.07, 95% CI 0.02, 0.13, P\u0026thinsp;=\u0026thinsp;0.006). Glut9i appears to lower blood glucose (β=-0.03, 95% CI -0.05, -0.01, P\u0026thinsp;=\u0026thinsp;0.013), decrease diastolic blood pressure (β=-0.03, 95% CI -0.05, -0.01, P\u0026thinsp;=\u0026thinsp;0.005), and increase high-density lipoprotein (β\u0026thinsp;=\u0026thinsp;0.02, 95% CI 0.00, 0.03, P\u0026thinsp;=\u0026thinsp;0.011) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Detailed MR analysis results can be found in Supplementary Tables\u0026nbsp;4. The MR analysis reveals no apparent pleiotropy or heterogeneity (Supplementary Table\u0026nbsp;4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results suggest that URAT1i reduces the risk of heart failure, lowers systolic blood pressure, decreases high-density lipoprotein levels, and increases fasting blood glucose. Additionally, GLUT9i is associated with decreased fasting blood glucose, decreased diastolic blood pressure, and increased high-density lipoprotein levels. These findings are consistent with another MR analysis indicating that uric acid-lowering therapy may provide cardiovascular benefits in preventing heart failure[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCompared to patients without hyperuricemia or gout, those with hyperuricemia or gout are more likely to develop heart failure[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Benzbromarone (a URAT1i) has shown significant improvement in diastolic dysfunction in comparison to the control group[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Dotinurad, as a highly selective URAT1i, has been marketed in Japan. Treatment with dotinurad for 24 weeks has been beneficial in impacting arterial stiffness and oxidative stress, leading to blood pressure reduction[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Dotinurad significantly attenuates high-fat diet-induced cardiac fibrosis, inflammatory response, and cardiac dysfunction. It may represent a promising therapeutic candidate for heart failure[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the renal tubules, GLUT9 transports uric acid at a rate 45\u0026ndash;60 times faster than glucose, and it has been demonstrated that GLUT9-mediated uric acid transport is enhanced by glucose and, to a lesser extent, by fructose[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The MR results from this study also GLUT9i can lower blood glucose levels, corroborating previous research findings. A prior MR analysis regarding GLUT9 gene variants suggested that a reduction in serum uric acid has a causal effect in lowering blood pressure[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. While the precise pathways linking serum uric acid to elevated blood pressure have not been fully elucidated, previous studies have proposed several potential mechanisms. These include renal vascular constriction due to microvascular diseases, impaired endothelial function or compliance, and disturbances in sodium and volume homeostasis[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In mouse models specifically engineered with a kidney-specific knockout of GLUT9, a slight decrease was observed in both diastolic and systolic blood pressure. Furthermore, in liver-specific GLUT9 knockout mice, there was an improvement in Metabolic associated fatty liver disease and suppression of hepatic expression of key genes involved in lipogenesis[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, the impact of GLUT9 inhibition on high-density lipoprotein levels still lacks comprehensive research and needs further investigation.\u003c/p\u003e \u003cp\u003eCompared to observational studies, this study has clear advantages. MR analysis, utilizing genetic information as a tool for causal inference studies, can yield statistically convincing results. This method allows clinicians to sidestep the complexities and high costs associated with randomized clinical trials and alleviates common ethical concerns in clinical settings. However, this study also presents several limitations: The drug-MR approach cannot fully emulate the real-life pharmacodynamics of a drug. The analysis was centered on the impact of the drug through uric acid reduction, disregarding other possible mechanisms of the drug's action. Additionally, the side effects stemming from the drug's metabolism could not be evaluated. The study exclusively involved European populations and did not stratify by gender. Hence, the findings might not be universally applicable to other ethnic groups or specific to one gender. Similar to other MR analyses, the reliability of the results could be compromised by the unknown pleiotropy of SNPs. These limitations highlight the necessity for a cautious interpretation of the findings and suggest areas for future research to explore and validate the outcomes further.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBoth URAT1i and GLUT9i are effective treatments for gout, and GLUT9i has the added benefits of lowering fasting glucose, reducing diastolic blood pressure, and increasing high-density lipoprotein levels. For patients suffering from gout in conjunction with conditions like hyperglycemia, dyslipidemia, and hypertension, GLUT9i may represent a more promising therapeutic approach.\u003c/p\u003e"},{"header":"Statements and Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eUrate's GWAS data is available at CKDGEN: http://ckdgen.imbi.uni-freiburg.de. Blood lipid of GWAS from http://csg.sph.umich.edu/willer/public/glgc-lipids2021. Other GWAS data can be accessed at the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk) for the following conditions and factors. Gout: ebi-a-GCST90038687, Heart Failure: ebi-a-GCST009541, Myocardial Infarction: ebi-a-GCST90018877, Ischemic Stroke: ebi-a-GCST90018864, Venous Thromboembolism: finn-b-I9_VTE, Fasting Glucose: ebi-a-GCST90002232, Systolic Blood Pressure: ebi-a-GCST90029011, Diastolic Blood Pressure: ebi-a-GCST90029010.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by funding from the Natural Science Foundation of Tianjin (No. 23JCYBJC00700).\u003c/p\u003e\n\u003cp\u003eAuthors' contributions\u003c/p\u003e\n\u003cp\u003eThe manuscript has been read and approved by all of the authors. Qian Xu: Data curation, Writing-Original draft preparation. Xinyu Liang and Wei Shi: Visualization. Huafeng Zhang Writing-Guiding and Reviewing.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eWe extend our sincere gratitude to the researchers who have shared their GWAS data, making this study possible, and we extend our gratitude to the FINN database for their support and contribution.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRichette P, Bardin T: \u003cstrong\u003eGout\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2010, \u003cstrong\u003e375\u003c/strong\u003e(9711):318-328.\u003c/li\u003e\n\u003cli\u003eDalbeth N, Merriman TR, Stamp LK: \u003cstrong\u003eGout\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2016, \u003cstrong\u003e388\u003c/strong\u003e(10055):2039-2052.\u003c/li\u003e\n\u003cli\u003eChoi HK, Curhan G: \u003cstrong\u003eIndependent impact of gout on mortality and risk for coronary heart disease\u003c/strong\u003e. \u003cem\u003eCirculation \u003c/em\u003e2007, \u003cstrong\u003e116\u003c/strong\u003e(8):894-900.\u003c/li\u003e\n\u003cli\u003eDe Vera MA, Rahman MM, Bhole V, Kopec JA, Choi HK: \u003cstrong\u003eIndependent impact of gout on the risk of acute myocardial infarction among elderly women: a population-based study\u003c/strong\u003e. \u003cem\u003eAnn Rheum Dis \u003c/em\u003e2010, \u003cstrong\u003e69\u003c/strong\u003e(6):1162-1164.\u003c/li\u003e\n\u003cli\u003eGupta MK, Singh JA: \u003cstrong\u003eCardiovascular Disease in Gout and the Protective Effect of Treatments Including Urate-Lowering Therapy\u003c/strong\u003e. \u003cem\u003eDrugs \u003c/em\u003e2019, \u003cstrong\u003e79\u003c/strong\u003e(5):531-541.\u003c/li\u003e\n\u003cli\u003eBardin T, Richette P: \u003cstrong\u003eImpact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options\u003c/strong\u003e. \u003cem\u003eBMC Med \u003c/em\u003e2017, \u003cstrong\u003e15\u003c/strong\u003e(1):123.\u003c/li\u003e\n\u003cli\u003eCipolletta E, Tata LJ, Nakafero G, Avery AJ, Mamas MA, Abhishek A: \u003cstrong\u003eAssociation Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout\u003c/strong\u003e. \u003cem\u003eJAMA \u003c/em\u003e2022, \u003cstrong\u003e328\u003c/strong\u003e(5):440-450.\u003c/li\u003e\n\u003cli\u003eDalbeth N, Gosling AL, Gaffo A, Abhishek A: \u003cstrong\u003eGout\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2021, \u003cstrong\u003e397\u003c/strong\u003e(10287):1843-1855.\u003c/li\u003e\n\u003cli\u003eHoy SM: \u003cstrong\u003eLesinurad: First Global Approval\u003c/strong\u003e. \u003cem\u003eDrugs \u003c/em\u003e2016, \u003cstrong\u003e76\u003c/strong\u003e(4):509-516.\u003c/li\u003e\n\u003cli\u003eTanaka A, Taguchi I, Hisauchi I, Yoshida H, Shimabukuro M, Hongo H, Ishikawa T, Kadokami T, Yagi S, Sata M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eClinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA)\u003c/strong\u003e. \u003cem\u003eEur J Med Res \u003c/em\u003e2023, \u003cstrong\u003e28\u003c/strong\u003e(1):238.\u003c/li\u003e\n\u003cli\u003eSawada S, Kajiyama K, Shida H, Kimura R, Nakazato Y, Iguchi T, Oniyama Y, Ishiguro C, Uyama Y: \u003cstrong\u003eCardiovascular risk of urate-lowering drugs: A study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan\u003c/strong\u003e. \u003cem\u003eClin Transl Sci \u003c/em\u003e2023, \u003cstrong\u003e16\u003c/strong\u003e(2):206-215.\u003c/li\u003e\n\u003cli\u003eLin HC, Daimon M, Wang CH, Ho Y, Uang YS, Chiang SJ, Wang LH: \u003cstrong\u003eAllopurinol, benzbromarone and risk of coronary heart disease in gout patients: A population-based study\u003c/strong\u003e. \u003cem\u003eInt J Cardiol \u003c/em\u003e2017, \u003cstrong\u003e233\u003c/strong\u003e:85-90.\u003c/li\u003e\n\u003cli\u003eChen JH, Lan JL, Cheng CF, Liang WM, Lin HY, Tsay GJ, Yeh WT, Pan WH: \u003cstrong\u003eEffect of Urate-lowering Therapy on the Risk of Cardiovascular Disease and All-cause Mortality in Patients with Gout: A Case-matched Cohort Study\u003c/strong\u003e. \u003cem\u003eJ Rheumatol \u003c/em\u003e2015, \u003cstrong\u003e42\u003c/strong\u003e(9):1694-1701.\u003c/li\u003e\n\u003cli\u003eCupido AJ, Reeskamp LF, Hingorani AD, Finan C, Asselbergs FW, Hovingh GK, Schmidt AF: \u003cstrong\u003eJoint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study\u003c/strong\u003e. \u003cem\u003eJAMA Cardiol \u003c/em\u003e2022, \u003cstrong\u003e7\u003c/strong\u003e(9):955-964.\u003c/li\u003e\n\u003cli\u003eWang M, Zhang Z, Georgakis MK, Karhunen V, Liu D: \u003cstrong\u003eThe Impact of Genetically Proxied AMPK Activation, the Target of Metformin, on Functional Outcome Following Ischemic Stroke\u003c/strong\u003e. \u003cem\u003eJ Stroke \u003c/em\u003e2023, \u003cstrong\u003e25\u003c/strong\u003e(2):266-271.\u003c/li\u003e\n\u003cli\u003eLi Y, Xiao W, Huang N, Zhuang Z, Zhang L, Wang W, Song Z, Zhao Y, Dong X, Xu M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe effects of blood pressure and antihypertensive drugs on heart failure: A Mendelian randomization study\u003c/strong\u003e. \u003cem\u003eNutr Metab Cardiovasc Dis \u003c/em\u003e2023, \u003cstrong\u003e33\u003c/strong\u003e(7):1420-1428.\u003c/li\u003e\n\u003cli\u003eTin A, Marten J, Halperin Kuhns VL, Li Y, Wuttke M, Kirsten H, Sieber KB, Qiu C, Gorski M, Yu Z\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eTarget genes, variants, tissues and transcriptional pathways influencing human serum urate levels\u003c/strong\u003e. \u003cem\u003eNat Genet \u003c/em\u003e2019, \u003cstrong\u003e51\u003c/strong\u003e(10):1459-1474.\u003c/li\u003e\n\u003cli\u003eDonertas HM, Fabian DK, Valenzuela MF, Partridge L, Thornton JM: \u003cstrong\u003eCommon genetic associations between age-related diseases\u003c/strong\u003e. \u003cem\u003eNat Aging \u003c/em\u003e2021, \u003cstrong\u003e1\u003c/strong\u003e(4):400-412.\u003c/li\u003e\n\u003cli\u003eShah S, Henry A, Roselli C, Lin H, Sveinbjornsson G, Fatemifar G, Hedman AK, Wilk JB, Morley MP, Chaffin MD\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure\u003c/strong\u003e. \u003cem\u003eNat Commun \u003c/em\u003e2020, \u003cstrong\u003e11\u003c/strong\u003e(1):163.\u003c/li\u003e\n\u003cli\u003eSakaue S, Kanai M, Tanigawa Y, Karjalainen J, Kurki M, Koshiba S, Narita A, Konuma T, Yamamoto K, Akiyama M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eA cross-population atlas of genetic associations for 220 human phenotypes\u003c/strong\u003e. \u003cem\u003eNat Genet \u003c/em\u003e2021, \u003cstrong\u003e53\u003c/strong\u003e(10):1415-1424.\u003c/li\u003e\n\u003cli\u003eChen J, Spracklen CN, Marenne G, Varshney A, Corbin LJ, Luan J, Willems SM, Wu Y, Zhang X, Horikoshi M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe trans-ancestral genomic architecture of glycemic traits\u003c/strong\u003e. \u003cem\u003eNat Genet \u003c/em\u003e2021, \u003cstrong\u003e53\u003c/strong\u003e(6):840-860.\u003c/li\u003e\n\u003cli\u003eLoh PR, Kichaev G, Gazal S, Schoech AP, Price AL: \u003cstrong\u003eMixed-model association for biobank-scale datasets\u003c/strong\u003e. \u003cem\u003eNat Genet \u003c/em\u003e2018, \u003cstrong\u003e50\u003c/strong\u003e(7):906-908.\u003c/li\u003e\n\u003cli\u003eGraham SE, Clarke SL, Wu KH, Kanoni S, Zajac GJM, Ramdas S, Surakka I, Ntalla I, Vedantam S, Winkler TW\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe power of genetic diversity in genome-wide association studies of lipids\u003c/strong\u003e. \u003cem\u003eNature \u003c/em\u003e2021, \u003cstrong\u003e600\u003c/strong\u003e(7890):675-679.\u003c/li\u003e\n\u003cli\u003eYang F, Hu T, Cui H: \u003cstrong\u003eSerum urate and heart failure: a bidirectional Mendelian randomization study\u003c/strong\u003e. \u003cem\u003eEur J Prev Cardiol \u003c/em\u003e2022, \u003cstrong\u003e29\u003c/strong\u003e(11):1570-1578.\u003c/li\u003e\n\u003cli\u003eHan Y, Cao Y, Han X, Di H, Yin Y, Wu J, Zhang Y, Zeng X: \u003cstrong\u003eHyperuricemia and gout increased the risk of long-term mortality in patients with heart failure: insights from the National Health and Nutrition Examination Survey\u003c/strong\u003e. \u003cem\u003eJ Transl Med \u003c/em\u003e2023, \u003cstrong\u003e21\u003c/strong\u003e(1):463.\u003c/li\u003e\n\u003cli\u003eKe J, Pan J, Lin H, Han Z, Gu J: \u003cstrong\u003eUric acid-lowering therapy with benzbromarone in hypertension with asymptomatic hyperuricemia: a randomized study focusing left ventricular diastolic function\u003c/strong\u003e. \u003cem\u003eCurr Med Res Opin \u003c/em\u003e2023, \u003cstrong\u003e39\u003c/strong\u003e(7):947-953.\u003c/li\u003e\n\u003cli\u003eYanai H, Katsuyama H, Hakoshima M, Adachi H: \u003cstrong\u003eUrate Transporter 1 Can Be a Therapeutic Target Molecule for Chronic Kidney Disease and Diabetic Kidney Disease: A Retrospective Longitudinal Study\u003c/strong\u003e. \u003cem\u003eBiomedicines \u003c/em\u003e2023, \u003cstrong\u003e11\u003c/strong\u003e(2).\u003c/li\u003e\n\u003cli\u003eTanaka Y, Nagoshi T, Takahashi H, Oi Y, Yasutake R, Yoshii A, Kimura H, Kashiwagi Y, Tanaka TD, Shimoda M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eURAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease\u003c/strong\u003e. \u003cem\u003eiScience \u003c/em\u003e2023, \u003cstrong\u003e26\u003c/strong\u003e(9):107730.\u003c/li\u003e\n\u003cli\u003eCaulfield MJ, Munroe PB, O\u0026apos;Neill D, Witkowska K, Charchar FJ, Doblado M, Evans S, Eyheramendy S, Onipinla A, Howard P\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eSLC2A9 is a high-capacity urate transporter in humans\u003c/strong\u003e. \u003cem\u003ePLoS Med \u003c/em\u003e2008, \u003cstrong\u003e5\u003c/strong\u003e(10):e197.\u003c/li\u003e\n\u003cli\u003eParsa A, Brown E, Weir MR, Fink JC, Shuldiner AR, Mitchell BD, McArdle PF: \u003cstrong\u003eGenotype-based changes in serum uric acid affect blood pressure\u003c/strong\u003e. \u003cem\u003eKidney Int \u003c/em\u003e2012, \u003cstrong\u003e81\u003c/strong\u003e(5):502-507.\u003c/li\u003e\n\u003cli\u003eKhosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ: \u003cstrong\u003eHyperuricemia induces endothelial dysfunction\u003c/strong\u003e. \u003cem\u003eKidney Int \u003c/em\u003e2005, \u003cstrong\u003e67\u003c/strong\u003e(5):1739-1742.\u003c/li\u003e\n\u003cli\u003eMaxwell AJ, Bruinsma KA: \u003cstrong\u003eUric acid is closely linked to vascular nitric oxide activity. Evidence for mechanism of association with cardiovascular disease\u003c/strong\u003e. \u003cem\u003eJ Am Coll Cardiol \u003c/em\u003e2001, \u003cstrong\u003e38\u003c/strong\u003e(7):1850-1858.\u003c/li\u003e\n\u003cli\u003eZeng H, Tang C, Lin B, Yu M, Wang X, Wang J, Chen S, Yu C: \u003cstrong\u003eThe regulation effect of GLUT9/SLC2A9 on intrahepatic uric acid level and metabolic associated fatty liver disease\u003c/strong\u003e. \u003cem\u003eHepatol Int \u003c/em\u003e2022, \u003cstrong\u003e16\u003c/strong\u003e(5):1064-1074.\u003c/li\u003e\n\u003cli\u003eAuberson M, Stadelmann S, Stoudmann C, Seuwen K, Koesters R, Thorens B, Bonny O: \u003cstrong\u003eSLC2A9 (GLUT9) mediates urate reabsorption in the mouse kidney\u003c/strong\u003e. \u003cem\u003ePflugers Arch \u003c/em\u003e2018, \u003cstrong\u003e470\u003c/strong\u003e(12):1739-1751.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Mendelian Randomization, Drug, Cardiovascular Diseases, Hyperuricemia, Gout","lastPublishedDoi":"10.21203/rs.3.rs-6055930/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6055930/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe strong association between hyperuricemia and cardiovascular diseases prompts this study to investigate the effects of uric acid-lowering drugs, GLUT9 and URAT1 inhibitors (GLUT9i and URAT1i), on cardiovascular diseases using Mendelian randomization (MR) analyses.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIn GWAS data, SNPs strongly associated with blood uric acid within 100kb regions around the GLUT9 and URAT1 genes are identified, serving as proxies for the targeted effects of genes on uric acid. Subsequently, these SNPs were utilized for MR analyses with gout, common cardiovascular diseases (heart failure, myocardial infarction, ischemic stroke, venous thromboembolism), and their risk factors (blood glucose, lipid levels, blood pressure). MR-Egger was employed for pleiotropy testing, and Cochran's Q test was utilized for heterogeneity testing to ensure the robustness of the MR analysis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBoth URAT1i and GLUT9i are effective drugs for gout. URAT1i is associated with a reduced risk of heart failure (OR\u0026thinsp;=\u0026thinsp;0.76, 95% CI 0.63, 0.92, P\u0026thinsp;=\u0026thinsp;0.004), decreased diastolic blood pressure (β=-0.07, 95% CI -0.13, 0.00, P\u0026thinsp;=\u0026thinsp;0.048), reduced high-density lipoprotein levels (β=-0.05, 95% CI -0.10, -0.01, P\u0026thinsp;=\u0026thinsp;0.016), and increased fasting blood glucose levels (β\u0026thinsp;=\u0026thinsp;0.07, 95% CI 0.02, 0.13, P\u0026thinsp;=\u0026thinsp;0.006). Conversely, GLUT9i leads to reductions in fasting blood glucose (β =-0.03, 95% CI -0.05, -0.01, P\u0026thinsp;=\u0026thinsp;0.013) and diastolic blood pressure (β =-0.03, 95% CI -0.05, -0.01, P\u0026thinsp;=\u0026thinsp;0.005), and increases in high-density lipoprotein (β\u0026thinsp;=\u0026thinsp;0.02, 95% CI 0.00, 0.03, P\u0026thinsp;=\u0026thinsp;0.011)\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFor patients suffering from gout in conjunction with conditions like hyperglycemia, dyslipidemia, and hypertension, GLUT9i may represent a more promising therapeutic approach.\u003c/p\u003e","manuscriptTitle":"The Effects of GLUT9 and URAT1 Inhibitors on Cardiovascular Diseases: A Drug-Targeted Mendelian Randomization Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-21 16:57:27","doi":"10.21203/rs.3.rs-6055930/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a366534b-f767-4252-9a60-669d174dddea","owner":[],"postedDate":"February 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-09T16:00:21+00:00","versionOfRecord":{"articleIdentity":"rs-6055930","link":"https://doi.org/10.1007/s11255-025-04594-z","journal":{"identity":"international-urology-and-nephrology","isVorOnly":false,"title":"International Urology and Nephrology"},"publishedOn":"2025-06-06 15:57:13","publishedOnDateReadable":"June 6th, 2025"},"versionCreatedAt":"2025-02-21 16:57:27","video":"","vorDoi":"10.1007/s11255-025-04594-z","vorDoiUrl":"https://doi.org/10.1007/s11255-025-04594-z","workflowStages":[]},"version":"v1","identity":"rs-6055930","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6055930","identity":"rs-6055930","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}