{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:39:08Z","timestamp":1761863948048,"version":"3.37.3"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2018,12,14]],"date-time":"2018-12-14T00:00:00Z","timestamp":1544745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,3,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>The mechanism explaining the inverse association between renal urate and albumin excretion remains unclear. First, we evaluated the impact of candidate variants in the main urate transporter genes (i.e., SLC2A9, SLC22A12, ABCG2) on the association between fractional excretion of uric acid (FEUA) and urinary albumin\/creatinine ratio (uACR). Second, we examined uromodulin and sodium excretion as mediators of the association between FEUA and uACR.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We performed cross-sectional analysis of 737 French Canadians from the CARTaGENE cohort, a random sample of the Quebec population aged 40\u201369 years (a total of 20,004 individuals). Individuals with available genotyping and urinary data were obtained from a sub-study including gender-matched pairs with high and low Framingham Risk Score and vascular rigidity index. We further excluded individuals with an estimated glomerular filtration rate &amp;lt;60 ml\/min\/1.73 m2, glycosuria, and use of confounding medication. A spot urine sample was analyzed. Genotyping was performed using the Illumina Omni2.5\u20138 BeadChips. Genetic variants were analyzed using an additive model.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Final analyses included 593 individuals (45.5% of men; mean age 54.3 \u00b1 8.6). We observed an antagonistic interaction between rs13129697 variant of the SLC2A9 gene and FEUA tertiles on uACR (P = 0.002). Using the mediation analysis, uromodulin explained 32%, fractional excretion of sodium (FENa) 44%, and uromodulin together with FENa explained 70% of the inverse relationship between FEUA and uACR. Bootstrapping process confirmed the role of both mediators.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Our data suggest that the association of albuminuria with decreased renal urate excretion may be modified by the transporter SLC2A9, and mediated by uromodulin and sodium handling.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ajh\/hpy190","type":"journal-article","created":{"date-parts":[[2018,12,11]],"date-time":"2018-12-11T04:17:27Z","timestamp":1544501847000},"page":"384-392","source":"Crossref","is-referenced-by-count":3,"title":["Uromodulin in a Pathway Between Decreased Renal Urate Excretion and Albuminuria"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4436-5023","authenticated-orcid":false,"given":"Alena","family":"Krajcoviechova","sequence":"first","affiliation":[{"name":"Center for Cardiovascular Prevention, First Faculty of Medicine and Thomayer Hospital, Charles University in Prague, Prague, Czech Republic"},{"name":"Centre de recherche du CHUM, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois-Christophe","family":"Marois-Blanchet","sequence":"additional","affiliation":[{"name":"Centre de recherche du CHUM, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Troyanov","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, H\u00f4pital du Sacr\u00e9-Coeur de Montr\u00e9al, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Harvey","sequence":"additional","affiliation":[{"name":"Centre de recherche du CHUM, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre","family":"Dumas","sequence":"additional","affiliation":[{"name":"Centre de recherche du CHUM, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanne","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Centre de recherche du CHUM, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata","family":"Cifkova","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Prevention, First Faculty of Medicine and Thomayer Hospital, Charles University in Prague, Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Awadalla","sequence":"additional","affiliation":[{"name":"Centre hospitalier universitaire Sainte-Justine, CHU Sainte-Justine, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Madore","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, H\u00f4pital du Sacr\u00e9-Coeur de Montr\u00e9al, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Hamet","sequence":"additional","affiliation":[{"name":"Centre de recherche du CHUM, Montr\u00e9al, Quebec, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2018,12,14]]},"reference":[{"key":"2022111018425016300_CIT0001","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.cca.2018.05.046","article-title":"Uric acid and cardiovascular disease","volume":"484","author":"Ndrepepa","year":"2018","journal-title":"Clin Chim Acta"},{"key":"2022111018425016300_CIT0002","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1161\/01.HYP.0000161184.10873.ea","article-title":"Serum uric acid and target organ damage in primary hypertension","volume":"45","author":"Viazzi","year":"2005","journal-title":"Hypertension"},{"key":"2022111018425016300_CIT0003","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1093\/ajh\/hpw098","article-title":"The impact of blood pressure and visceral adiposity on the association of serum uric acid with albuminuria in adults without full metabolic syndrome","volume":"29","author":"Krajcoviechova","year":"2016","journal-title":"Am J Hypertens"},{"key":"2022111018425016300_CIT0004","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1111\/j.1464-5491.2011.03515.x","article-title":"Serum uric acid is related to cardiovascular events and correlates with N-terminal pro-B-type natriuretic peptide and albuminuria in patients with diabetes mellitus","volume":"29","author":"Resl","year":"2012","journal-title":"Diabet Med"},{"key":"2022111018425016300_CIT0005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.medcli.2008.07.008","article-title":"Association between serum uric acid, metabolic syndrome and microalbuminuria in previously untreated essential hypertensive patients","volume":"132","author":"Rodilla","year":"2009","journal-title":"Med Clin (Barc)"},{"key":"2022111018425016300_CIT0006","doi-asserted-by":"crossref","first-page":"e000613","DOI":"10.1161\/JAHA.113.000613","article-title":"The association of albuminuria with tubular reabsorption of uric acid: results from a general population cohort","volume":"3","author":"Scheven","year":"2014","journal-title":"J Am Heart Assoc"},{"key":"2022111018425016300_CIT0007","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1093\/ajh\/hpw198","article-title":"Response to letter to the editor entitled oxidative stress participates in the associations between serum uric acid and albuminuria in obesity","volume":"30","author":"Krajcoviechova","year":"2017","journal-title":"Am J Hypertens"},{"key":"2022111018425016300_CIT0008","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s11926-012-0240-z","article-title":"Regulation of uric acid excretion by the kidney","volume":"14","author":"Lipkowitz","year":"2012","journal-title":"Curr Rheumatol Rep"},{"key":"2022111018425016300_CIT0009","doi-asserted-by":"crossref","first-page":"e197","DOI":"10.1371\/journal.pmed.0050197","article-title":"SLC2A9 is a high-capacity urate transporter in humans","volume":"5","author":"Caulfield","year":"2008","journal-title":"PLoS Med"},{"key":"2022111018425016300_CIT0010","doi-asserted-by":"crossref","first-page":"e1000504","DOI":"10.1371\/journal.pgen.1000504","article-title":"Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations","volume":"5","author":"Kolz","year":"2009","journal-title":"PLoS Genet"},{"key":"2022111018425016300_CIT0011","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/ng.2500","article-title":"Genome-wide association analyses identify 18 new loci associated with serum urate concentrations","volume":"45","author":"K\u00f6ttgen","year":"2013","journal-title":"Nat Genet"},{"key":"2022111018425016300_CIT0012","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1681\/ASN.2013090950","article-title":"The proximal tubule and albuminuria: really","volume":"25","author":"Dickson","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"2022111018425016300_CIT0013","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1161\/01.HYP.0000028589.66335.AA","article-title":"Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity","volume":"40","author":"Watanabe","year":"2002","journal-title":"Hypertension"},{"key":"2022111018425016300_CIT0014","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1161\/01.HYP.23.2.195","article-title":"Microalbuminuria in salt-sensitive patients. A marker for renal and cardiovascular risk factors","volume":"23","author":"Bigazzi","year":"1994","journal-title":"Hypertension"},{"key":"2022111018425016300_CIT0015","doi-asserted-by":"crossref","first-page":"e1001177","DOI":"10.1371\/journal.pgen.1001177","article-title":"Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension","volume":"6","author":"Padmanabhan","year":"2010","journal-title":"PLoS Genet"},{"key":"2022111018425016300_CIT0016","doi-asserted-by":"crossref","first-page":"62","DOI":"10.2215\/CJN.04770415","article-title":"Clinical, genetic, and urinary factors associated with uromodulin excretion","volume":"11","author":"Troyanov","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"2022111018425016300_CIT0017","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1161\/HYPERTENSIONAHA.114.03132","article-title":"Uromodulin, an emerging novel pathway for blood pressure regulation and hypertension","volume":"64","author":"Padmanabhan","year":"2014","journal-title":"Hypertension"},{"key":"2022111018425016300_CIT0018","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1093\/ije\/dys160","article-title":"Cohort profile of the CARTaGENE study: Quebec\u2019s population-based biobank for public health and personalized genomics","volume":"42","author":"Awadalla","year":"2013","journal-title":"Int J Epidemiol"},{"key":"2022111018425016300_CIT0019","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1097\/HJH.0000000000000475","article-title":"Association of age-dependent height and bone mineral density decline with increased arterial stiffness and rate of fractures in hypertensive individuals","volume":"33","author":"El-Bikai","year":"2015","journal-title":"J Hypertens"},{"key":"2022111018425016300_CIT0020","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1093\/ndt\/gft345","article-title":"Determination of uromodulin in human urine: influence of storage and processing","volume":"29","author":"Youhanna","year":"2014","journal-title":"Nephrol Dial Transplant"},{"key":"2022111018425016300_CIT0021","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation PLINK: rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"2022111018425016300_CIT0022","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1534\/genetics.114.164350","article-title":"fastSTRUCTURE: variational inference of population structure in large SNP data sets","volume":"197","author":"Raj","year":"2014","journal-title":"Genetics"},{"key":"2022111018425016300_CIT0023","doi-asserted-by":"crossref","first-page":"3934","DOI":"10.1038\/ncomms4934","article-title":"Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel","volume":"5","author":"Delaneau","year":"2014","journal-title":"Nat Commun"},{"key":"2022111018425016300_CIT0024","doi-asserted-by":"crossref","first-page":"e1000529","DOI":"10.1371\/journal.pgen.1000529","article-title":"A flexible and accurate genotype imputation method for the next generation of genome-wide association studies","volume":"5","author":"Howie","year":"2009","journal-title":"PLoS Genet"},{"key":"2022111018425016300_CIT0025","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1002\/gepi.20328","article-title":"Does strong linkage disequilibrium guarantee redundant association results","volume":"32","author":"Nielsen","year":"2008","journal-title":"Genet Epidemiol"},{"key":"2022111018425016300_CIT0026","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1161\/CIRCGENETICS.109.934455","article-title":"Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors","volume":"3","author":"Yang","year":"2010","journal-title":"Circ Cardiovasc Genet"},{"key":"2022111018425016300_CIT0027","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1016\/S0140-6736(08)61343-4","article-title":"Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study","volume":"372","author":"Dehghan","year":"2008","journal-title":"Lancet"},{"key":"2022111018425016300_CIT0028","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1002\/art.23752","article-title":"Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order amish","volume":"58","author":"McArdle","year":"2008","journal-title":"Arthritis Rheum"},{"key":"2022111018425016300_CIT0029","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/art.21499","article-title":"Association of the human urate transporter 1 with reduced renal uric acid excretion and hyperuricemia in a German Caucasian population","volume":"54","author":"Graessler","year":"2006","journal-title":"Arthritis Rheum"},{"key":"2022111018425016300_CIT0030","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41588-018-0047-6","article-title":"Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases","volume":"50","author":"Kanai","year":"2018","journal-title":"Nat Genet"},{"key":"2022111018425016300_CIT0031","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1002\/sim.2165","article-title":"Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure","volume":"24","author":"Tobin","year":"2005","journal-title":"Stat Med"},{"key":"2022111018425016300_CIT0032","doi-asserted-by":"crossref","first-page":"879","DOI":"10.3758\/BRM.40.3.879","article-title":"Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models","volume":"40","author":"Preacher","year":"2008","journal-title":"Behav Res Methods"},{"key":"2022111018425016300_CIT0033","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3389\/fgene.2013.00279","article-title":"Genome-wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to Mexican Americans","volume":"4","author":"Voruganti","year":"2013","journal-title":"Front Genet"},{"key":"2022111018425016300_CIT0034","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/ejhg.2013.264","article-title":"Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians","volume":"22","author":"Voruganti","year":"2014","journal-title":"Eur J Hum Genet"},{"key":"2022111018425016300_CIT0035","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1046\/j.1523-1755.2002.00300.x","article-title":"Gene expression profile of renal proximal tubules regulated by proteinuria","volume":"61","author":"Nakajima","year":"2002","journal-title":"Kidney Int"},{"key":"2022111018425016300_CIT0036","doi-asserted-by":"crossref","DOI":"10.1111\/ijcp.13048","article-title":"Uric acid and cardiovascular risk: what genes can say","volume":"72","author":"Kei","year":"2018","journal-title":"Int J Clin Pract"},{"key":"2022111018425016300_CIT0037","doi-asserted-by":"crossref","first-page":"70","DOI":"10.2215\/CJN.04230415","article-title":"Associations of urinary uromodulin with clinical characteristics and markers of tubular function in the general population","volume":"11","author":"Pruijm","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"2022111018425016300_CIT0038","doi-asserted-by":"crossref","first-page":"30200","DOI":"10.1074\/jbc.M111.222968","article-title":"Activation of the bumetanide-sensitive Na+,K+,2Cl- cotransporter (NKCC2) is facilitated by Tamm-Horsfall protein in a chloride-sensitive manner","volume":"286","author":"Mutig","year":"2011","journal-title":"J Biol Chem"},{"key":"2022111018425016300_CIT0039","doi-asserted-by":"crossref","first-page":"F1062","DOI":"10.1152\/ajprenal.00233.2017","article-title":"Tamm-Horsfall protein\/uromodulin deficiency elicits tubular compensatory responses leading to hypertension and hyperuricemia","volume":"314","author":"Liu","year":"2018","journal-title":"Am J Physiol Renal Physiol"},{"key":"2022111018425016300_CIT0040","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/sj.ki.5000210","article-title":"RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in the kidney","volume":"69","author":"Sachetelli","year":"2006","journal-title":"Kidney Int"},{"key":"2022111018425016300_CIT0041","doi-asserted-by":"crossref","first-page":"278","DOI":"10.5414\/CN109005","article-title":"Association of urinary uromodulin with kidney function decline and mortality: the health ABC study","volume":"87","author":"Garimella","year":"2017","journal-title":"Clin Nephrol"},{"key":"2022111018425016300_CIT0042","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1097\/HJH.0b013e328349de25","article-title":"Uromodulin gene variant is associated with type 2 diabetic nephropathy","volume":"29","author":"Ahluwalia","year":"2011","journal-title":"J Hypertens"},{"key":"2022111018425016300_CIT0043","doi-asserted-by":"crossref","first-page":"e30456","DOI":"10.1371\/journal.pone.0030456","article-title":"Extra-renal elimination of uric acid via intestinal efflux transporter BCRP\/ABCG2","volume":"7","author":"Hosomi","year":"2012","journal-title":"PLoS One"}],"container-title":["American Journal of Hypertension"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/32\/4\/384\/46949983\/ajh_32_4_384.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajh\/article-pdf\/32\/4\/384\/46949983\/ajh_32_4_384.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,13]],"date-time":"2024-07-13T05:49:27Z","timestamp":1720849767000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajh\/article\/32\/4\/384\/5245514"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,14]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,12,14]]},"published-print":{"date-parts":[[2019,3,16]]}},"URL":"https:\/\/doi.org\/10.1093\/ajh\/hpy190","relation":{},"ISSN":["0895-7061","1941-7225"],"issn-type":[{"type":"print","value":"0895-7061"},{"type":"electronic","value":"1941-7225"}],"subject":[],"published-other":{"date-parts":[[2019,4]]},"published":{"date-parts":[[2018,12,14]]}}}