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Gout: HELP
Articles by Anna Kottgen
Based on 16 articles published since 2009
(Why 16 articles?)
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Between 2009 and 2019, Anna Köttgen wrote the following 16 articles about Gout.
 
+ Citations + Abstracts
1 Review ABCG transporters and disease. 2011

Woodward, Owen M / Köttgen, Anna / Köttgen, Michael. ·Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. ·FEBS J · Pubmed #21554546.

ABSTRACT: ATP-binding cassette (ABC) transporters form a large family of transmembrane proteins that facilitate the transport of specific substrates across membranes in an ATP-dependent manner. Transported substrates include lipids, lipopolysaccharides, amino acids, peptides, proteins, inorganic ions, sugars and xenobiotics. Despite this broad array of substrates, the physiological substrate of many ABC transporters has remained elusive. ABC transporters are divided into seven subfamilies, A-G, based on sequence similarity and domain organization. Here we review the role of members of the ABCG subfamily in human disease and how the identification of disease genes helped to determine physiological substrates for specific ABC transporters. We focus on the recent discovery of mutations in ABCG2 causing hyperuricemia and gout, which has led to the identification of urate as a physiological substrate for ABCG2.

2 Article Gout in Older Adults: The Atherosclerosis Risk in Communities Study. 2016

Burke, Bridget Teevan / Köttgen, Anna / Law, Andrew / Grams, Morgan / Baer, Alan N / Coresh, Josef / McAdams-DeMarco, Mara A. ·Department of Epidemiology, JHU Bloomberg School of Public Health, Baltimore, Maryland. · Department of Epidemiology, JHU Bloomberg School of Public Health, Baltimore, Maryland. Division of Nephrology, University Medical Center Freiburg, Germany. · Department of Surgery. · Division of Nephrology, and. · Division of Rheumatology, JHU School of Medicine, Baltimore, Maryland. · Department of Epidemiology, JHU Bloomberg School of Public Health, Baltimore, Maryland. Department of Surgery, mara@jhu.edu. ·J Gerontol A Biol Sci Med Sci · Pubmed #26714568.

ABSTRACT: BACKGROUND: It is unclear whether traditional and genetic risk factors in middle age predict the onset of gout in older age. METHODS: We studied the incidence of gout in older adults using the Atherosclerosis Risk in Communities study, a prospective U.S. population-based cohort of middle-aged adults enrolled between 1987 and 1989 with ongoing follow-up. A genetic urate score was formed from common urate-associated single nucleotide polymorphisms for eight genes. The adjusted hazard ratio and 95% confidence interval of incident gout by traditional and genetic risk factors in middle age were estimated using a Cox proportional hazards model. RESULTS: The cumulative incidence from middle age to age 65 was 8.6% in men and 2.5% in women; by age 75 the cumulative incidence was 11.8% and 5.0%. In middle age, increased adiposity, beer intake, protein intake, smoking status, hypertension, diuretic use, and kidney function (but not sex) were associated with an increased gout risk in older age. In addition, a 100 µmol/L increase in genetic urate score was associated with a 3.29-fold (95% confidence interval: 1.63-6.63) increased gout risk in older age. CONCLUSIONS: These findings suggest that traditional and genetic risk factors in middle age may be useful for identifying those at risk of gout in older age.

3 Article Physical Function, Hyperuricemia, and Gout in Older Adults. 2015

Burke, Bridget Teevan / Köttgen, Anna / Law, Andrew / Windham, Beverly Gwen / Segev, Dorry / Baer, Alan N / Coresh, Josef / McAdams-DeMarco, Mara A. ·Johns Hopkins University, Baltimore, Maryland. · Johns Hopkins University, Baltimore, Maryland, and University of Freiburg, Freiburg, Germany. · University of Mississippi Medical Center, Jackson. ·Arthritis Care Res (Hoboken) · Pubmed #26138016.

ABSTRACT: OBJECTIVE: Gout prevalence is high in older adults and those affected are at risk of physical disability, yet it is unclear whether they have worse physical function. METHODS: We studied gout, hyperuricemia, and physical function in 5,819 older adults (age ≥65 years) attending the 2011-2013 Atherosclerosis Risk in Communities Study visit, a prospective US population-based cohort. Differences in lower extremity function (Short Physical Performance Battery [SPPB] and 4-meter walking speed) and upper extremity function (grip strength) by gout status and by hyperuricemia prevalence were estimated in adjusted ordinal logistic regression (SPPB) and linear regression (walking speed and grip strength) models. Lower scores or times signify worse function. The prevalence of poor physical performance (first quartile) by gout and hyperuricemia was estimated using adjusted modified Poisson regression. RESULTS: Ten percent of participants reported a history of gout and 21% had hyperuricemia. There was no difference in grip strength by history of gout (P = 0.77). Participants with gout performed worse on the SPPB test; they had 0.77 times (95% confidence interval [95% CI] 0.65, 0.90, P = 0.001) the prevalence odds of a 1-unit increase in SPPB score and were 1.18 times (95% CI 1.07, 1.32, P = 0.002) more likely to have poor SPPB performance. Participants with a history of gout had slower walking speed (mean difference -0.03; 95% CI -0.05, -0.01, P < 0.001) and were 1.19 times (95% CI 1.06, 1.34, P = 0.003) more likely to have poor walking speed. Similarly, SPPB score and walking speed, but not grip strength, were worse in participants with hyperuricemia. CONCLUSION: Older adults with gout and hyperuricemia are more likely to have worse lower extremity, but not upper extremity, function.

4 Article Modulation of genetic associations with serum urate levels by body-mass-index in humans. 2015

Huffman, Jennifer E / Albrecht, Eva / Teumer, Alexander / Mangino, Massimo / Kapur, Karen / Johnson, Toby / Kutalik, Zoltán / Pirastu, Nicola / Pistis, Giorgio / Lopez, Lorna M / Haller, Toomas / Salo, Perttu / Goel, Anuj / Li, Man / Tanaka, Toshiko / Dehghan, Abbas / Ruggiero, Daniela / Malerba, Giovanni / Smith, Albert V / Nolte, Ilja M / Portas, Laura / Phipps-Green, Amanda / Boteva, Lora / Navarro, Pau / Johansson, Asa / Hicks, Andrew A / Polasek, Ozren / Esko, Tõnu / Peden, John F / Harris, Sarah E / Murgia, Federico / Wild, Sarah H / Tenesa, Albert / Tin, Adrienne / Mihailov, Evelin / Grotevendt, Anne / Gislason, Gauti K / Coresh, Josef / D'Adamo, Pio / Ulivi, Sheila / Vollenweider, Peter / Waeber, Gerard / Campbell, Susan / Kolcic, Ivana / Fisher, Krista / Viigimaa, Margus / Metter, Jeffrey E / Masciullo, Corrado / Trabetti, Elisabetta / Bombieri, Cristina / Sorice, Rossella / Döring, Angela / Reischl, Eva / Strauch, Konstantin / Hofman, Albert / Uitterlinden, Andre G / Waldenberger, Melanie / Wichmann, H-Erich / Davies, Gail / Gow, Alan J / Dalbeth, Nicola / Stamp, Lisa / Smit, Johannes H / Kirin, Mirna / Nagaraja, Ramaiah / Nauck, Matthias / Schurmann, Claudia / Budde, Kathrin / Farrington, Susan M / Theodoratou, Evropi / Jula, Antti / Salomaa, Veikko / Sala, Cinzia / Hengstenberg, Christian / Burnier, Michel / Mägi, Reedik / Klopp, Norman / Kloiber, Stefan / Schipf, Sabine / Ripatti, Samuli / Cabras, Stefano / Soranzo, Nicole / Homuth, Georg / Nutile, Teresa / Munroe, Patricia B / Hastie, Nicholas / Campbell, Harry / Rudan, Igor / Cabrera, Claudia / Haley, Chris / Franco, Oscar H / Merriman, Tony R / Gudnason, Vilmundur / Pirastu, Mario / Penninx, Brenda W / Snieder, Harold / Metspalu, Andres / Ciullo, Marina / Pramstaller, Peter P / van Duijn, Cornelia M / Ferrucci, Luigi / Gambaro, Giovanni / Deary, Ian J / Dunlop, Malcolm G / Wilson, James F / Gasparini, Paolo / Gyllensten, Ulf / Spector, Tim D / Wright, Alan F / Hayward, Caroline / Watkins, Hugh / Perola, Markus / Bochud, Murielle / Kao, W H Linda / Caulfield, Mark / Toniolo, Daniela / Völzke, Henry / Gieger, Christian / Köttgen, Anna / Vitart, Veronique. ·Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, United Kingdom. · Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. · King's College London, St. Thomas' Hospital Campus, London, United Kingdom. · Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland. · William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. · Institute for Maternal and Child Health-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) "Burlo Garofolo", Trieste, Italy; University of Trieste, Trieste, Italy. · Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy. · Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom; Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom. · Estonian Genome Center, University of Tartu, Tartu, Estonia. · Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland. · Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America. · Clinical Research Branch, National Institute on Aging, Baltimore, MD, United States of America. · Member of Netherlands Consortium for Healthy Aging (NCHA) sponsored by Netherlands Genomics Initiative (NGI), Leiden, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. · Institute of Genetics and Biophysics "A. Buzzati-Traverso"-Consiglio Nazionale delle Ricerche (CNR), Naples, Italy. · Biology and Genetics section, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy. · Icelandic Heart Association Research Institute, Kopavogur, Iceland; University of Iceland, Reykjavik, Iceland. · Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. · Institute of Population Genetics, National Research Council of Italy, Sassari, Italy. · Department of Biochemistry, University of Otago, Dunedin, New Zealand. · Uppsala Clinical Research Center, Uppsala University Hospital, Upsalla, Sweden; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, 751 85, Sweden. · Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy; Affiliated Institute of the University of Lübeck, Lübeck, Germany. · Faculty of Medicine, University of Split, Croatia, Soltanska 2, Split, 21000, Croatia. · Estonian Genome Center, University of Tartu, Tartu, Estonia; Broad Institute, Cambridge, MA, United States of America; Children's Hospital Boston, Boston, MA, United States of America. · Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom; Medical Genetics Section, University of Edinburgh Centre for Genomics and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, Edinburgh, United Kingdom. · Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom. · Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Edinburgh, United Kingdom; Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom. · Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany. · Icelandic Heart Association Research Institute, Kopavogur, Iceland. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America; Welch Center for Prevention, Epidemiology and Clinical Research, John Hopkins University, Baltimore, MD, United States of America. · Institute for Maternal and Child Health-Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) "Burlo Garofolo", Trieste, Italy. · Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland. · Tallinn University of Technology, Department of Biomedical Engineering, Chair of Medical Physics, Tallinn, Estonia; Centre of Cardiology, North Estonia Medical Centre, Tallinn, Estonia. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. · Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany. · Institute of Epidemiology I, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany; Klinikum Grosshadern, Munich, Germany. · Bone and Joint Research Group, Department of Medicine, University of Auckland, Auckland, New Zealand. · Department of Medicine, University of Otago, Christchurch, New Zealand. · Department of Psychiatry/EMGO Institute, VU University Medical Centre, Amsterdam, the Netherlands. · Laboratory of Genetics, National Institute on Aging (NIA), Baltimore, MD, United States of America. · Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Turku, Finland. · University Hospital Regensburg, Regensburg, Germany. · Department of Medicine, Nephrology Division, Lausanne University Hospital, Lausanne, Switzerland. · Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-University, Munich, Germany. · Max Planck Institute of Psychiatry, Munich, Germany. · Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Turku, Finland; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; University of Helsinki, Institute of Molecular Medicine, Helsinki, Finland. · Department of Mathematics and Informatics, Università di Cagliari, Cagliari, Italy; Department of Statistics, Universidad Carlos III de Madrid, Madrid, Spain. · Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom. · Faculty of Medicine, University of Split, Croatia, Soltanska 2, Split, 21000, Croatia; Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, United Kingdom. · Queen Mary, University of London, London, United Kingdom. · Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands; Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus MC, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. · Department of Epidemiology, Subdivision Genetic Epidemiology, Erasmus MC, Rotterdam, The Netherlands. · Institute of Internal Medicine, Renal Program, Columbus-Gemelli University Hospital, Catholic University, Rome, Italy. · Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, 751 85, Sweden. · on behalf of PROCARDIS; Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. · Estonian Genome Center, University of Tartu, Tartu, Estonia; Department of Chronic Disease Prevention, National Institute for Health and Welfare (THL), Helsinki, Finland; University of Helsinki, Institute of Molecular Medicine, Helsinki, Finland. · University Institute of Social and Preventive Medicine, Lausanne, Switzerland. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America; Renal Division, Freiburg University Hospital, Freiburg, Germany. ·PLoS One · Pubmed #25811787.

ABSTRACT: We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

5 Article Plasma Urate and Risk of a Hospital Stay with AKI: The Atherosclerosis Risk in Communities Study. 2015

Greenberg, Keiko I / McAdams-DeMarco, Mara A / Köttgen, Anna / Appel, Lawrence J / Coresh, Josef / Grams, Morgan E. ·Departments of Medicine and kgreenb4@jhmi.edu. · Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland; · Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland; Renal Division, University Medical Center Freiburg, Freiburg, Germany; and. · Departments of Medicine and Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland; Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland. · Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland; Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland. ·Clin J Am Soc Nephrol · Pubmed #25717072.

ABSTRACT: BACKGROUND AND OBJECTIVES: Higher urate levels are associated with higher risk of CKD, but the association between urate and AKI is less established. This study evaluated the risk of hospitalized AKI associated with urate concentrations in a large population-based cohort. To explore whether urate itself causes kidney injury, the study also evaluated the relationship between a genetic urate score and AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 11,011 participants from the Atherosclerosis Risk in Communities study were followed from 1996-1998 (baseline) to 2010. The association between baseline plasma urate and risk of hospitalized AKI, adjusted for known AKI risk factors, was determined using Cox regression. Interactions of urate with gout and CKD were tested. Mendelian randomization was performed using a published genetic urate score among the participants with genetic data (n=7553). RESULTS: During 12 years of follow-up, 823 participants were hospitalized with AKI. Overall, mean participant age was 63.3 years, mean eGFR was 86.3 ml/min per 1.73 m(2), and mean plasma urate was 5.6 mg/dl. In patients with plasma urate >5.0 mg/dl, there was a 16% higher risk of hospitalized AKI for each 1-mg/dl higher urate (adjusted hazard ratio, 1.16; 95% confidence interval, 1.10 to 1.23; P<0.001). When stratified by history of gout, the association between higher urate and AKI was significant only in participants without a history of gout (P for interaction=0.02). There was no interaction of CKD and urate with AKI, nor was there an association between genetic urate score and AKI. CONCLUSIONS: Plasma urate >5.0 mg/dl was independently associated with risk of hospitalized AKI; however, Mendelian randomization did not provide evidence for a causal role of urate in AKI. Further research is needed to determine whether lowering plasma urate might reduce AKI risk.

6 Article Prevalence and correlates of gout in a large cohort of patients with chronic kidney disease: the German Chronic Kidney Disease (GCKD) study. 2015

Jing, Jiaojiao / Kielstein, Jan T / Schultheiss, Ulla T / Sitter, Thomas / Titze, Stephanie I / Schaeffner, Elke S / McAdams-DeMarco, Mara / Kronenberg, Florian / Eckardt, Kai-Uwe / Köttgen, Anna / Anonymous6300811. ·Renal Division, Medical Center-University of Freiburg, Freiburg, Germany. · Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany. · Department of Medicine, Ludwig-Maximilians-University Hospital, Munich, Germany. · Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany. · Division of Nephrology and Intensive Care Medicine, Charité University Medicine, Berlin, Germany. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA. · Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria. ·Nephrol Dial Transplant · Pubmed #25395390.

ABSTRACT: BACKGROUND: Reduced kidney function is a risk factor for hyperuricaemia and gout, but limited information on the burden of gout is available from studies of patients with chronic kidney disease (CKD). We therefore examined the prevalence and correlates of gout in the large prospective observational German Chronic Kidney Disease (GCKD) study. METHODS: Data from 5085 CKD patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) of 30-<60 mL/min/1.73 m(2) or eGFR ≥60 and overt proteinuria at recruitment and non-missing values for self-reported gout, medications and urate measurements from a central laboratory were evaluated. RESULTS: The overall prevalence of gout was 24.3%, and increased from 16.0% in those with eGFR ≥60 mL/min/1.73 m(2) to 35.6% in those with eGFR <30. Of those with self-reported gout, 30.7% of individuals were not currently taking any gout medication and among gout patients on urate lowering therapy, 47.2% still showed hyperuricaemia. Factors associated with gout were serum urate, lower eGFR, advanced age, male sex, higher body mass index and waist-to-hip ratio, higher triglyceride and C-reactive protein (CRP) concentrations, alcohol intake and diuretics use. While lower eGFR categories showed significant associations with gout in multivariable-adjusted models (prevalence ratio 1.46 for eGFR <30 compared with eGFR ≥60, 95% confidence interval 1.21-1.77), associations between gout and higher urinary albumin-to-creatinine ratio in this CKD population were not significant. CONCLUSIONS: Self-reported gout is common among patients with CKD and lower GFR is strongly associated with gout. Pharmacological management of gout in patients with CKD is suboptimal. Prospective follow-up will show whether gout and hyperuricaemia increase the risk of CKD progression and cardiovascular events in the GCKD study.

7 Article Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study. 2013

Zhang, Lili / Spencer, Kylee L / Voruganti, V Saroja / Jorgensen, Neal W / Fornage, Myriam / Best, Lyle G / Brown-Gentry, Kristin D / Cole, Shelley A / Crawford, Dana C / Deelman, Ewa / Franceschini, Nora / Gaffo, Angelo L / Glenn, Kimberly R / Heiss, Gerardo / Jenny, Nancy S / Kottgen, Anna / Li, Qiong / Liu, Kiang / Matise, Tara C / North, Kari E / Umans, Jason G / Kao, W H Linda. · ·Am J Epidemiol · Pubmed #23552988.

ABSTRACT: A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

8 Article Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. 2013

Köttgen, Anna / Albrecht, Eva / Teumer, Alexander / Vitart, Veronique / Krumsiek, Jan / Hundertmark, Claudia / Pistis, Giorgio / Ruggiero, Daniela / O'Seaghdha, Conall M / Haller, Toomas / Yang, Qiong / Tanaka, Toshiko / Johnson, Andrew D / Kutalik, Zoltán / Smith, Albert V / Shi, Julia / Struchalin, Maksim / Middelberg, Rita P S / Brown, Morris J / Gaffo, Angelo L / Pirastu, Nicola / Li, Guo / Hayward, Caroline / Zemunik, Tatijana / Huffman, Jennifer / Yengo, Loic / Zhao, Jing Hua / Demirkan, Ayse / Feitosa, Mary F / Liu, Xuan / Malerba, Giovanni / Lopez, Lorna M / van der Harst, Pim / Li, Xinzhong / Kleber, Marcus E / Hicks, Andrew A / Nolte, Ilja M / Johansson, Asa / Murgia, Federico / Wild, Sarah H / Bakker, Stephan J L / Peden, John F / Dehghan, Abbas / Steri, Maristella / Tenesa, Albert / Lagou, Vasiliki / Salo, Perttu / Mangino, Massimo / Rose, Lynda M / Lehtimäki, Terho / Woodward, Owen M / Okada, Yukinori / Tin, Adrienne / Müller, Christian / Oldmeadow, Christopher / Putku, Margus / Czamara, Darina / Kraft, Peter / Frogheri, Laura / Thun, Gian Andri / Grotevendt, Anne / Gislason, Gauti Kjartan / Harris, Tamara B / Launer, Lenore J / McArdle, Patrick / Shuldiner, Alan R / Boerwinkle, Eric / Coresh, Josef / Schmidt, Helena / Schallert, Michael / Martin, Nicholas G / Montgomery, Grant W / Kubo, Michiaki / Nakamura, Yusuke / Tanaka, Toshihiro / Munroe, Patricia B / Samani, Nilesh J / Jacobs, David R / Liu, Kiang / D'Adamo, Pio / Ulivi, Sheila / Rotter, Jerome I / Psaty, Bruce M / Vollenweider, Peter / Waeber, Gerard / Campbell, Susan / Devuyst, Olivier / Navarro, Pau / Kolcic, Ivana / Hastie, Nicholas / Balkau, Beverley / Froguel, Philippe / Esko, Tõnu / Salumets, Andres / Khaw, Kay Tee / Langenberg, Claudia / Wareham, Nicholas J / Isaacs, Aaron / Kraja, Aldi / Zhang, Qunyuan / Wild, Philipp S / Scott, Rodney J / Holliday, Elizabeth G / Org, Elin / Viigimaa, Margus / Bandinelli, Stefania / Metter, Jeffrey E / Lupo, Antonio / Trabetti, Elisabetta / Sorice, Rossella / Döring, Angela / Lattka, Eva / Strauch, Konstantin / Theis, Fabian / Waldenberger, Melanie / Wichmann, H-Erich / Davies, Gail / Gow, Alan J / Bruinenberg, Marcel / Anonymous4691162 / Stolk, Ronald P / Kooner, Jaspal S / Zhang, Weihua / Winkelmann, Bernhard R / Boehm, Bernhard O / Lucae, Susanne / Penninx, Brenda W / Smit, Johannes H / Curhan, Gary / Mudgal, Poorva / Plenge, Robert M / Portas, Laura / Persico, Ivana / Kirin, Mirna / Wilson, James F / Mateo Leach, Irene / van Gilst, Wiek H / Goel, Anuj / Ongen, Halit / Hofman, Albert / Rivadeneira, Fernando / Uitterlinden, Andre G / Imboden, Medea / von Eckardstein, Arnold / Cucca, Francesco / Nagaraja, Ramaiah / Piras, Maria Grazia / Nauck, Matthias / Schurmann, Claudia / Budde, Kathrin / Ernst, Florian / Farrington, Susan M / Theodoratou, Evropi / Prokopenko, Inga / Stumvoll, Michael / Jula, Antti / Perola, Markus / Salomaa, Veikko / Shin, So-Youn / Spector, Tim D / Sala, Cinzia / Ridker, Paul M / Kähönen, Mika / Viikari, Jorma / Hengstenberg, Christian / Nelson, Christopher P / Anonymous4701162 / Anonymous4711162 / Anonymous4721162 / Anonymous4731162 / Meschia, James F / Nalls, Michael A / Sharma, Pankaj / Singleton, Andrew B / Kamatani, Naoyuki / Zeller, Tanja / Burnier, Michel / Attia, John / Laan, Maris / Klopp, Norman / Hillege, Hans L / Kloiber, Stefan / Choi, Hyon / Pirastu, Mario / Tore, Silvia / Probst-Hensch, Nicole M / Völzke, Henry / Gudnason, Vilmundur / Parsa, Afshin / Schmidt, Reinhold / Whitfield, John B / Fornage, Myriam / Gasparini, Paolo / Siscovick, David S / Polašek, Ozren / Campbell, Harry / Rudan, Igor / Bouatia-Naji, Nabila / Metspalu, Andres / Loos, Ruth J F / van Duijn, Cornelia M / Borecki, Ingrid B / Ferrucci, Luigi / Gambaro, Giovanni / Deary, Ian J / Wolffenbuttel, Bruce H R / Chambers, John C / März, Winfried / Pramstaller, Peter P / Snieder, Harold / Gyllensten, Ulf / Wright, Alan F / Navis, Gerjan / Watkins, Hugh / Witteman, Jacqueline C M / Sanna, Serena / Schipf, Sabine / Dunlop, Malcolm G / Tönjes, Anke / Ripatti, Samuli / Soranzo, Nicole / Toniolo, Daniela / Chasman, Daniel I / Raitakari, Olli / Kao, W H Linda / Ciullo, Marina / Fox, Caroline S / Caulfield, Mark / Bochud, Murielle / Gieger, Christian. ·Renal Division, Freiburg University Hospital, Freiburg, Germany. anna.koettgen@uniklinik-freiburg.de ·Nat Genet · Pubmed #23263486.

ABSTRACT: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

9 Article A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study. 2013

McAdams-DeMarco, Mara A / Maynard, Janet W / Baer, Alan N / Kao, Linda W / Kottgen, Anna / Coresh, Josef. ·Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 2024 E. Monument St, Suite B-319, Baltimore, MD 21287, USA. mmcadams@jhsph.edu ·Ann Rheum Dis · Pubmed #22753387.

ABSTRACT: OBJECTIVE: To test for a urate gene-by-diuretic interaction on incident gout. METHODS: The Atherosclerosis Risk in Communities Study is a prospective population-based cohort of 15 792 participants recruited from four US communities (1987-1989). Participants with hypertension and available single nucleotide polymorphism (SNP) genotype data were included. A genetic urate score (GUS) was created from common urate-associated SNPs for eight genes. Gout incidence was self-reported. Using logistic regression, the authors estimated the adjusted OR of incident gout by diuretic use, stratified by GUS median. RESULTS: Of 3524 participants with hypertension, 33% used a diuretic and 3.1% developed gout. The highest 9-year cumulative incidence of gout was in those with GUS above the median and taking a thiazide or loop diuretic (6.3%). Compared with no thiazide or loop diuretic use, their use was associated with an OR of 0.40 (95% CI 0.14 to 1.15) among those with a GUS below the median and 2.13 (95% CI 1.23 to 3.67) for those with GUS above the median; interaction p=0.006. When investigating the genes separately, SLC22A11 and SLC2A9 showed a significant interaction, consistent with the former encoding an organic anion/dicarboxylate exchanger, which mediates diuretic transport in the kidney. CONCLUSIONS: Participants who were genetically predisposed to hyperuricaemia were susceptible to developing gout when taking thiazide or loop diuretics, an effect not evident among those without a genetic predisposition. These findings argue for a potential benefit of genotyping individuals with hypertension to assess gout risk, relative in part to diuretic use.

10 Article Incident gout in women and association with obesity in the Atherosclerosis Risk in Communities (ARIC) Study. 2012

Maynard, Janet W / McAdams DeMarco, Mara A / Baer, Alan N / Köttgen, Anna / Folsom, Aaron R / Coresh, Josef / Gelber, Allan C. ·Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Am J Med · Pubmed #22571781.

ABSTRACT: BACKGROUND: We hypothesized that women with early- and mid-adult life obesity, as well as high mid-adult life waist-to-hip ratios, and high weight gain during adulthood, experience a greater incidence of gout. METHODS: We examined the incidence of gout in the Atherosclerosis Risk in Communities Study, a population-based biracial cohort comprised of individuals aged 45-65 years at baseline (1987-1989). A total of 6263 women without prior history of gout were identified. We examined the association of body mass index (BMI) and obesity at cohort entry and at age 25 years, waist-to-hip ratio, and weight change with gout incidence (1996-1998). RESULTS: Over 9 years of follow-up, 106 women developed gout. The cumulative incidence of gout, by age 70 years, according to BMI category at baseline of <25, 25-29.9, 30-34.9, and ≥35 kg/m(2), was 1.9, 3.6, 7.9, and 11.8%, respectively (P <.001). Obese women (BMI ≥30) at baseline had an adjusted 2.4-fold greater risk of developing gout than nonobese women (95% confidence interval [CI], 1.53-3.68). This association was attenuated after further adjustment for urate levels. Further, early adult obesity in women was associated with a 2.8-fold increased risk of gout compared with nonobese women (95% CI, 1.33-6.09), which remained statistically significant after baseline urate adjustment. There was a graded association between each anthropometric measure, including weight gain, with incident gout (each P for trend <.001). The results were similar in black and white women. CONCLUSIONS: In a large cohort of black and white women, obesity in early- and mid-adulthood, and weight gain during this interval, were each independent risk factors for incident gout in women.

11 Article Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. 2011

Tin, Adrienne / Woodward, Owen M / Kao, Wen Hong Linda / Liu, Ching-Ti / Lu, Xiaoning / Nalls, Michael A / Shriner, Daniel / Semmo, Mariam / Akylbekova, Ermeg L / Wyatt, Sharon B / Hwang, Shih-Jen / Yang, Qiong / Zonderman, Alan B / Adeyemo, Adebowale A / Palmer, Cameron / Meng, Yan / Reilly, Muredach / Shlipak, Michael G / Siscovick, David / Evans, Michele K / Rotimi, Charles N / Flessner, Michael F / Köttgen, Michael / Cupples, L Adrienne / Fox, Caroline S / Köttgen, Anna / Anonymous3940700. ·Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA. ·Hum Mol Genet · Pubmed #21768215.

ABSTRACT: Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.

12 Article Obesity and younger age at gout onset in a community-based cohort. 2011

DeMarco, Mara A McAdams / Maynard, Janet W / Huizinga, Mary Margret / Baer, Alan N / Köttgen, Anna / Gelber, Allan C / Coresh, Josef. ·Johns Hopkins University, 2024 East Monument Street, Baltimore,MD 21287, USA. mmcadams@jhsph.edu ·Arthritis Care Res (Hoboken) · Pubmed #21485022.

ABSTRACT: OBJECTIVE: Obesity is associated with gout risk. It is unclear whether obesity is associated with a younger age at gout onset. We examined whether obesity is related to age at gout onset and quantified the risk of incident gout by obesity status in the Campaign Against Cancer and Heart Disease (CLUE II) study, a longitudinal community-based cohort. METHODS: CLUE II began in 1989 as a cohort study of residents living within or surrounding Washington County, Maryland. Followup questionnaires queried whether each participant had been diagnosed as having gout by a health care professional. Among participants with gout, we assessed whether obesity was related to age at disease onset. We also ascertained the 18-year risk of incident gout according to obesity status (body mass index ≥30 kg/m(2) ) at baseline with cumulative incidence ratios (RRs) and 95% confidence intervals (95% CIs) from Poisson regression. RESULTS: Among the study population (n = 15,533), 517 persons developed incident gout. The prevalence of obesity at baseline was 16.2%. The overall mean age at gout onset was 59.3 years. The onset of gout was 3.1 years (95% CI 0.3, 5.8) earlier in those who were obese at baseline and 11.0 years earlier (95% CI 5.8, 16.1) in participants who were obese at age 21 years, as compared with the nonobese participants. The 18-year adjusted RR of gout in obese participants compared with nonobese participants was 1.92 (95% CI 1.55, 2.37). CONCLUSION: Obesity is not only a risk factor for incident gout but is associated with an earlier age at gout onset.

13 Article Reliability and sensitivity of the self-report of physician-diagnosed gout in the campaign against cancer and heart disease and the atherosclerosis risk in the community cohorts. 2011

McAdams, Mara A / Maynard, Janet W / Baer, Alan N / Köttgen, Anna / Clipp, Sandra / Coresh, Josef / Gelber, Allan C. ·Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21224, USA. agelber@jhmi.edu ·J Rheumatol · Pubmed #21123328.

ABSTRACT: OBJECTIVE: gout is often defined by self-report in epidemiologic studies. Yet the validity of self-reported gout is uncertain. We evaluated the reliability and sensitivity of the self-report of physician-diagnosed gout in the Campaign Against Cancer and Heart Disease (CLUE II) and the Atherosclerosis Risk in the Community (ARIC) cohorts. METHODS: the CLUE II cohort comprises 12,912 individuals who self-reported gout status on either the 2000, 2003, or 2007 questionnaires. We calculated reliability as the percentage of participants reporting having gout on more than 1 questionnaire using Cohen's κ statistic. The ARIC cohort comprises 11,506 individuals who self-reported gout status at visit 4. We considered a hospital discharge diagnosis of gout or use of a gout-specific medication as the standard against which to calculate the sensitivity of self-reported, physician-diagnosed gout. RESULTS: of the 437 CLUE II participants who self-reported physician-diagnosed gout in 2000, and subsequently answered the 2003 questionnaire, 75% reported gout in 2003 (κ = 0.73). Of the 271 participants who reported gout in 2000, 73% again reported gout at the 2007 followup questionnaire (κ = 0.63). In ARIC, 196 participants met the definition for gout prior to visit 4 and self-reported their gout status at visit 4. The sensitivity of a self-report of physician-diagnosed gout was 84%. Accuracy was similar across sex and race subgroups, but differed across hyperuricemia and education strata. CONCLUSION: these 2 population-based US cohorts suggest that self-report of physician-diagnosed gout has good reliability and sensitivity. Thus, self-report of a physician diagnosis of gout is appropriate for epidemiologic studies.

14 Article Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. 2010

Yang, Qiong / Köttgen, Anna / Dehghan, Abbas / Smith, Albert V / Glazer, Nicole L / Chen, Ming-Huei / Chasman, Daniel I / Aspelund, Thor / Eiriksdottir, Gudny / Harris, Tamara B / Launer, Lenore / Nalls, Michael / Hernandez, Dena / Arking, Dan E / Boerwinkle, Eric / Grove, Megan L / Li, Man / Linda Kao, W H / Chonchol, Michel / Haritunians, Talin / Li, Guo / Lumley, Thomas / Psaty, Bruce M / Shlipak, Michael / Hwang, Shih-Jen / Larson, Martin G / O'Donnell, Christopher J / Upadhyay, Ashish / van Duijn, Cornelia M / Hofman, Albert / Rivadeneira, Fernando / Stricker, Bruno / Uitterlinden, Andre G / Paré, Guillaume / Parker, Alex N / Ridker, Paul M / Siscovick, David S / Gudnason, Vilmundur / Witteman, Jacqueline C / Fox, Caroline S / Coresh, Josef. ·Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. ·Circ Cardiovasc Genet · Pubmed #20884846.

ABSTRACT: BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD). METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study. CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

15 Article The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people. 2010

Yamagishi, Kazumasa / Tanigawa, Takeshi / Kitamura, Akihiko / Köttgen, Anna / Folsom, Aaron R / Iso, Hiroyasu / Anonymous1710659. ·Department of Public Health Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan. ·Rheumatology (Oxford) · Pubmed #20421215.

ABSTRACT: OBJECTIVES: Recent genome-wide association and functional studies have shown that the ABCG2 gene encodes for a urate transporter, and a common causal ABCG2 variant, rs2231142, leads to elevated uric acid levels and prevalent gout among Whites and Blacks. We examined whether this finding is observed in a Japanese population, since Asians have a high reported prevalence of the T-risk allele. METHODS: A total of 3923 Japanese people from the Circulatory Risk in Communities Study aged 40-90 years were genotyped for rs2231142. Associations of the rs2231142 variant with serum uric acid levels and prevalence of gout and hyperuricaemia were examined. RESULTS: The frequency of the T-risk allele was 31% in this Japanese sample. Multivariable adjusted mean uric acid levels were 7-9 micromol/l higher for TG and TT than GG carriers (P-additive = 0.0006). The multivariable-adjusted odds ratio (OR) of prevalent gout was 1.37 (95% CI 0.68, 2.76) for TG and 4.37 (95% CI 1.98, 9.62) for TT compared with the GG carriers (P-additive = 0.001). When evaluating the combined outcome of hyperuricaemia and gout, the respective ORs were 1.40 (95% CI 1.04, 1.87) for TG and 1.88 (95% CI 1.23, 2.89) for TT carriers. The population attributable risk was 29% for gout and 19% for gout and/or hyperuricaemia. CONCLUSIONS: The association of the causal ABCG2 rs2231142 variant with uric acid levels and gout was confirmed in a sample of Japanese ancestry. Our study emphasizes the importance of this common causal variant in a population with a high risk allele frequency, especially as more Japanese adopt a Western lifestyle with a concomitant increase in mean serum uric acid levels.

16 Article Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. 2009

Woodward, Owen M / Köttgen, Anna / Coresh, Josef / Boerwinkle, Eric / Guggino, William B / Köttgen, Michael. ·Department of Physiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. ·Proc Natl Acad Sci U S A · Pubmed #19506252.

ABSTRACT: Genome-wide association studies (GWAS) have successfully identified common single nucleotide polymorphisms (SNPs) associated with a wide variety of complex diseases, but do not address gene function or establish causality of disease-associated SNPs. We recently used GWAS to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout, a consequence of elevated urate levels. Here we show using functional assays that human ATP-binding cassette, subfamily G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. We further show that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs2231142 by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wild-type ABCG2 (P < 0.001). Data from a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region and show highly significant associations with urate levels [whites: P = 10(-30), minor allele frequency (MAF) 0.11; blacks P = 10(-4), MAF 0.03] and gout (adjusted odds ratio 1.68 per risk allele, both races). Our data indicate that at least 10% of all gout cases in whites are attributable to this causal variant. With approximately 3 million US individuals suffering from often insufficiently treated gout, ABCG2 represents an attractive drug target. Our study completes the chain of evidence from association to causation and supports the common disease-common variant hypothesis in the etiology of gout.