@article {972, title = {Relationship of uric acid with progression of kidney disease.}, journal = {Am J Kidney Dis}, volume = {50}, year = {2007}, month = {2007 Aug}, pages = {239-47}, abstract = {

BACKGROUND: Uric acid levels are increased in patients with kidney dysfunction. We tested the hypothesis that uric acid may be associated with kidney disease progression.

STUDY DESIGN: Cohort study.

SETTING \& PARTICIPANTS: 5,808 participants of the Cardiovascular Health Study.

PREDICTOR: Uric acid levels.

OUTCOMES \& MEASUREMENTS: Kidney disease progression was defined as a decrease in estimated glomerular filtration rate (GFR) of 3 mL/min/1.73 m(2) per year or greater (>or=0.05 mL/s) and as incident chronic kidney disease (CKD). Measures of kidney function were estimated GFR using the Modification of Diet in Renal Disease Study equation.

RESULTS: Higher quintiles of uric acid levels were associated with greater prevalences of estimated GFR less than 60 mL/min/1.73 m(2) (<1.00 mL/s) of 7\%, 14\%, 12\%, 25\%, and 42\% for quintiles 1 (6.90 mg/dL [>410 micromol/L]), respectively. In comparison, there was only a modest, but significant, association between quintiles of uric acid levels and progression of kidney function decrease, with adjusted odds ratios of 1.0, 0.88 (95\% confidence interval [CI], 0.64 to 1.21), 1.23 (95\% CI, 0.87 to 1.75), 1.47 (95\% CI, 1.04 to 2.07), and 1.49 (95\% CI, 1.00 to 2.22) for quintiles 1 through 5, respectively. No significant association was found between uric acid level and incident CKD (adjusted odds ratio, 1.00; 95\% CI, 0.89 to 1.14).

LIMITATIONS: Measurements of albuminuria were not available.

CONCLUSIONS: Uric acid levels are associated strongly with prevalent CKD. In comparison, greater uric acid levels had a significant, but much weaker, association with progression of kidney disease.

}, keywords = {Aged, Aged, 80 and over, Cohort Studies, Cross-Sectional Studies, Disease Progression, Female, Glomerular Filtration Rate, Humans, Kidney Diseases, Male, Prospective Studies, Uric Acid}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2007.05.013}, author = {Chonchol, Michel and Shlipak, Michael G and Katz, Ronit and Sarnak, Mark J and Newman, Anne B and Siscovick, David S and Kestenbaum, Bryan and Carney, Jan Kirk and Fried, Linda F} } @article {1235, title = {Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Dec}, pages = {523-30}, 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{\textquoteright}s Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4{\texttimes}10(-8) to 2{\texttimes}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{\texttimes}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{\textquoteright}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.

}, keywords = {Cardiovascular Diseases, Coronary Disease, Female, Genetic Loci, Genome-Wide Association Study, Gout, Humans, Male, Risk Factors, Uric Acid}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.934455}, author = {Yang, Qiong and K{\"o}ttgen, Anna and Dehghan, Abbas and Smith, Albert V and Glazer, Nicole L and Chen, Ming-Huei and Chasman, Daniel I and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Launer, Lenore and Nalls, Michael and Hernandez, Dena and Arking, Dan E and Boerwinkle, Eric and Grove, Megan L and Li, Man and Linda Kao, W H and Chonchol, Michel and Haritunians, Talin and Li, Guo and Lumley, Thomas and Psaty, Bruce M and Shlipak, Michael and Hwang, Shih-Jen and Larson, Martin G and O{\textquoteright}Donnell, Christopher J and Upadhyay, Ashish and van Duijn, Cornelia M and Hofman, Albert and Rivadeneira, Fernando and Stricker, Bruno and Uitterlinden, Andr{\'e} G and Par{\'e}, Guillaume and Parker, Alex N and Ridker, Paul M and Siscovick, David S and Gudnason, Vilmundur and Witteman, Jacqueline C and Fox, Caroline S and Coresh, Josef} } @article {1305, title = {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.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Oct 15}, pages = {4056-68}, 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 {\texttimes} 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 {\texttimes} 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 {\texttimes} 10(-32)) and SLC22A12 (P= 2.1 {\texttimes} 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 {\texttimes} 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.

}, keywords = {Adult, African Americans, Aged, Animals, CHO Cells, Cricetinae, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Gout, Humans, Loss of Heterozygosity, Male, Middle Aged, Organic Anion Transporters, Organic Cation Transport Proteins, Polymorphism, Single Nucleotide, Uric Acid, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddr307}, author = {Tin, Adrienne and Woodward, Owen M and Kao, Wen Hong Linda and Liu, Ching-Ti and Lu, Xiaoning and Nalls, Michael A and Shriner, Daniel and Semmo, Mariam and Akylbekova, Ermeg L and Wyatt, Sharon B and Hwang, Shih-Jen and Yang, Qiong and Zonderman, Alan B and Adeyemo, Adebowale A and Palmer, Cameron and Meng, Yan and Reilly, Muredach and Shlipak, Michael G and Siscovick, David and Evans, Michele K and Rotimi, Charles N and Flessner, Michael F and K{\"o}ttgen, Michael and Cupples, L Adrienne and Fox, Caroline S and K{\"o}ttgen, Anna} } @article {1297, title = {The risk of Parkinson disease associated with urate in a community-based cohort of older adults.}, journal = {Neuroepidemiology}, volume = {36}, year = {2011}, month = {2011}, pages = {223-9}, abstract = {

BACKGROUND/AIMS: Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults.

METHODS: The association of baseline urate ({\textmu}mol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 {\textmu}mol/l), middle (300-500 {\textmu}mol/l), and high (>500 {\textmu}mol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD.

RESULTS: Women had significantly lower urate concentrations than did men [316.8 {\textmu}mol/l (SD 88.0) vs. 367.4 {\textmu}mol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 {\textmu}mol/l (OR 1.69, 95\% CI 1.03-2.78) but not for urate >500 {\textmu}mol/l (OR 1.55, 95\% CI 0.72-3.32) in men. A negative linear term was significant for urate <500 {\textmu}mol/l, and across the entire range a convex quadratic term was significant.

CONCLUSIONS: Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.

}, keywords = {Aged, California, Cohort Studies, Female, Humans, Male, Maryland, North Carolina, Parkinson Disease, Pennsylvania, Prospective Studies, Risk Factors, Sex Distribution, Sex Factors, Uric Acid}, issn = {1423-0208}, doi = {10.1159/000327748}, author = {Jain, S and Ton, T G and Boudreau, R M and Yang, M and Thacker, E L and Studenski, S and Longstreth, W T and Strotmeyer, E S and Newman, A B} } @article {6827, title = {Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study.}, journal = {Am J Epidemiol}, volume = {177}, year = {2013}, month = {2013 May 1}, pages = {923-32}, 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 {\texttimes} 10(-67), P = 3.98 {\texttimes} 10(-5), P = 6.97 {\texttimes} 10(-9), and P = 5.33 {\texttimes} 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 {\texttimes} 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 {\texttimes} 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 {\texttimes} 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.

}, keywords = {Adult, African Americans, Age Distribution, ATP-Binding Cassette Transporters, Comorbidity, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Gout, Hormone Replacement Therapy, Humans, Indians, North American, Male, Mexican Americans, Middle Aged, Neoplasm Proteins, Polymorphism, Genetic, Postmenopause, Sex Distribution, United States, Uric Acid}, issn = {1476-6256}, doi = {10.1093/aje/kws330}, author = {Zhang, Lili and Spencer, Kylee L and Voruganti, V Saroja and Jorgensen, Neal W and Fornage, Myriam and Best, Lyle G and Brown-Gentry, Kristin D and Cole, Shelley A and Crawford, Dana C and Deelman, Ewa and Franceschini, Nora and Gaffo, Angelo L and Glenn, Kimberly R and Heiss, Gerardo and Jenny, Nancy S and K{\"o}ttgen, Anna and Li, Qiong and Liu, Kiang and Matise, Tara C and North, Kari E and Umans, Jason G and Kao, W H Linda} } @article {6075, title = {Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Feb}, pages = {145-54}, 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.

}, keywords = {Analysis of Variance, European Continental Ancestry Group, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Glucose, Gout, Humans, Inhibins, Polymorphism, Single Nucleotide, Signal Transduction, Uric Acid}, issn = {1546-1718}, doi = {10.1038/ng.2500}, author = {K{\"o}ttgen, Anna and Albrecht, Eva and Teumer, Alexander and Vitart, Veronique and Krumsiek, Jan and Hundertmark, Claudia and Pistis, Giorgio and Ruggiero, Daniela and O{\textquoteright}Seaghdha, Conall M and Haller, Toomas and Yang, Qiong and Tanaka, Toshiko and Johnson, Andrew D and Kutalik, Zolt{\'a}n and Smith, Albert V and Shi, Julia and Struchalin, Maksim and Middelberg, Rita P S and Brown, Morris J and Gaffo, Angelo L and Pirastu, Nicola and Li, Guo and Hayward, Caroline and Zemunik, Tatijana and Huffman, Jennifer and Yengo, Loic and Zhao, Jing Hua and Demirkan, Ayse and Feitosa, Mary F and Liu, Xuan and Malerba, Giovanni and Lopez, Lorna M and van der Harst, Pim and Li, Xinzhong and Kleber, Marcus E and Hicks, Andrew A and Nolte, Ilja M and Johansson, Asa and Murgia, Federico and Wild, Sarah H and Bakker, Stephan J L and Peden, John F and Dehghan, Abbas and Steri, Maristella and Tenesa, Albert and Lagou, Vasiliki and Salo, Perttu and Mangino, Massimo and Rose, Lynda M and Lehtim{\"a}ki, Terho and Woodward, Owen M and Okada, Yukinori and Tin, Adrienne and M{\"u}ller, Christian and Oldmeadow, Christopher and Putku, Margus and Czamara, Darina and Kraft, Peter and Frogheri, Laura and Thun, Gian Andri and Grotevendt, Anne and Gislason, Gauti Kjartan and Harris, Tamara B and Launer, Lenore J and McArdle, Patrick and Shuldiner, Alan R and Boerwinkle, Eric and Coresh, Josef and Schmidt, Helena and Schallert, Michael and Martin, Nicholas G and Montgomery, Grant W and Kubo, Michiaki and Nakamura, Yusuke and Tanaka, Toshihiro and Munroe, Patricia B and Samani, Nilesh J and Jacobs, David R and Liu, Kiang and D{\textquoteright}Adamo, Pio and Ulivi, Sheila and Rotter, Jerome I and Psaty, Bruce M and Vollenweider, Peter and Waeber, G{\'e}rard and Campbell, Susan and Devuyst, Olivier and Navarro, Pau and Kolcic, Ivana and Hastie, Nicholas and Balkau, Beverley and Froguel, Philippe and Esko, T{\~o}nu and Salumets, Andres and Khaw, Kay Tee and Langenberg, Claudia and Wareham, Nicholas J and Isaacs, Aaron and Kraja, Aldi and Zhang, Qunyuan and Wild, Philipp S and Scott, Rodney J and Holliday, Elizabeth G and Org, Elin and Viigimaa, Margus and Bandinelli, Stefania and Metter, Jeffrey E and Lupo, Antonio and Trabetti, Elisabetta and Sorice, Rossella and D{\"o}ring, Angela and Lattka, Eva and Strauch, Konstantin and Theis, Fabian and Waldenberger, Melanie and Wichmann, H-Erich and Davies, Gail and Gow, Alan J and Bruinenberg, Marcel and Stolk, Ronald P and Kooner, Jaspal S and Zhang, Weihua and Winkelmann, Bernhard R and Boehm, Bernhard O and Lucae, Susanne and Penninx, Brenda W and Smit, Johannes H and Curhan, Gary and Mudgal, Poorva and Plenge, Robert M and Portas, Laura and Persico, Ivana and Kirin, Mirna and Wilson, James F and Mateo Leach, Irene and van Gilst, Wiek H and Goel, Anuj and Ongen, Halit and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Imboden, Medea and von Eckardstein, Arnold and Cucca, Francesco and Nagaraja, Ramaiah and Piras, Maria Grazia and Nauck, Matthias and Schurmann, Claudia and Budde, Kathrin and Ernst, Florian and Farrington, Susan M and Theodoratou, Evropi and Prokopenko, Inga and Stumvoll, Michael and Jula, Antti and Perola, Markus and Salomaa, Veikko and Shin, So-Youn and Spector, Tim D and Sala, Cinzia and Ridker, Paul M and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Hengstenberg, Christian and Nelson, Christopher P and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Singleton, Andrew B and Kamatani, Naoyuki and Zeller, Tanja and Burnier, Michel and Attia, John and Laan, Maris and Klopp, Norman and Hillege, Hans L and Kloiber, Stefan and Choi, Hyon and Pirastu, Mario and Tore, Silvia and Probst-Hensch, Nicole M and V{\"o}lzke, Henry and Gudnason, Vilmundur and Parsa, Afshin and Schmidt, Reinhold and Whitfield, John B and Fornage, Myriam and Gasparini, Paolo and Siscovick, David S and Polasek, Ozren and Campbell, Harry and Rudan, Igor and Bouatia-Naji, Nabila and Metspalu, Andres and Loos, Ruth J F and van Duijn, Cornelia M and Borecki, Ingrid B and Ferrucci, Luigi and Gambaro, Giovanni and Deary, Ian J and Wolffenbuttel, Bruce H R and Chambers, John C and M{\"a}rz, Winfried and Pramstaller, Peter P and Snieder, Harold and Gyllensten, Ulf and Wright, Alan F and Navis, Gerjan and Watkins, Hugh and Witteman, Jacqueline C M and Sanna, Serena and Schipf, Sabine and Dunlop, Malcolm G and T{\"o}njes, Anke and Ripatti, Samuli and Soranzo, Nicole and Toniolo, Daniela and Chasman, Daniel I and Raitakari, Olli and Kao, W H Linda and Ciullo, Marina and Fox, Caroline S and Caulfield, Mark and Bochud, Murielle and Gieger, Christian} } @article {6823, title = {Positive association of tomato consumption with serum urate: support for tomato consumption as an anecdotal trigger of gout flares.}, journal = {BMC Musculoskelet Disord}, volume = {16}, year = {2015}, month = {2015}, pages = {196}, abstract = {

BACKGROUND: Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels.

METHODS: Two thousand fifty one New Zealanders (of M{\={a}}ori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake.

RESULTS: Seventy one percent of people with gout reported having >=1 gout trigger food. Of these 20\% specifically mentioned tomatoes, the 4(th) most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (β = 0.66 μmolL(-1) increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: β = 0.84 μmolL(-1), P = 0.035; women: β = 0.59 μmolL (-1), P = 0.041).

CONCLUSIONS: While our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis.

}, keywords = {Adolescent, Adult, Aged, European Continental Ancestry Group, Female, Gout, Humans, Hyperuricemia, Lycopersicon esculentum, Male, Middle Aged, New Zealand, Oceanic Ancestry Group, Surveys and Questionnaires, Uric Acid, Young Adult}, issn = {1471-2474}, doi = {10.1186/s12891-015-0661-8}, author = {Flynn, Tanya J and Cadzow, Murray and Dalbeth, Nicola and Jones, Peter B and Stamp, Lisa K and Hindmarsh, Jennie Harr{\'e} and Todd, Alwyn S and Walker, Robert J and Topless, Ruth and Merriman, Tony R} } @article {6624, title = {Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study.}, journal = {Metabolism}, volume = {64}, year = {2015}, month = {2015 Mar}, pages = {438-46}, abstract = {

PURPOSE: Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults.

METHODS: 1963 men and 2729 women >=65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori.

RESULTS: There was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and >=6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95\% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women.

CONCLUSION: In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cohort Studies, Estrogen Replacement Therapy, Female, Health Surveys, Hip Fractures, Humans, Kaplan-Meier Estimate, Male, Prospective Studies, Risk, Sex Factors, United States, Uric Acid}, issn = {1532-8600}, doi = {10.1016/j.metabol.2014.11.006}, author = {Mehta, Tapan and B{\r u}zkov{\'a}, Petra and Sarnak, Mark J and Chonchol, Michel and Cauley, Jane A and Wallace, Erin and Fink, Howard A and Robbins, John and Jalal, Diana} } @article {7928, title = {Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 12}, pages = {4228}, abstract = {

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among <=19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 {\texttimes} 10) and SLC2A9 (p = 4.5 {\texttimes} 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 {\texttimes} 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

}, keywords = {Exome, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative, Humans, Kidney Function Tests, Meta-Analysis as Topic, Organic Anion Transporters, Organic Cation Transport Proteins, Protein Structure, Secondary, Uric Acid}, issn = {2041-1723}, doi = {10.1038/s41467-018-06620-4}, author = {Tin, Adrienne and Li, Yong and Brody, Jennifer A and Nutile, Teresa and Chu, Audrey Y and Huffman, Jennifer E and Yang, Qiong and Chen, Ming-Huei and Robinson-Cohen, Cassianne and Mace, Aurelien and Liu, Jun and Demirkan, Ayse and Sorice, Rossella and Sedaghat, Sanaz and Swen, Melody and Yu, Bing and Ghasemi, Sahar and Teumer, Alexanda and Vollenweider, Peter and Ciullo, Marina and Li, Meng and Uitterlinden, Andr{\'e} G and Kraaij, Robert and Amin, Najaf and van Rooij, Jeroen and Kutalik, Zolt{\'a}n and Dehghan, Abbas and McKnight, Barbara and van Duijn, Cornelia M and Morrison, Alanna and Psaty, Bruce M and Boerwinkle, Eric and Fox, Caroline S and Woodward, Owen M and K{\"o}ttgen, Anna} } @article {8046, title = {No causal effects of serum urate levels on the risk of chronic kidney disease: A Mendelian randomization study.}, journal = {PLoS Med}, volume = {16}, year = {2019}, month = {2019 01}, pages = {e1002725}, abstract = {

BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR).

METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 μmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95\% CI -2.86 to -1.11; P = 8.08 {\texttimes} 10(-6); odds ratio [OR] for CKD: 1.48; 95\% CI 1.32 to 1.65; P = 1.52 {\texttimes} 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99\% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study.

CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.

}, keywords = {Adult, Age Factors, Female, Genome-Wide Association Study, Glomerular Filtration Rate, Humans, Male, Mendelian Randomization Analysis, Renal Insufficiency, Chronic, Sex Factors, Uric Acid, Young Adult}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002725}, author = {Jordan, Daniel M and Choi, Hyon K and Verbanck, Marie and Topless, Ruth and Won, Hong-Hee and Nadkarni, Girish and Merriman, Tony R and Do, Ron} } @article {9006, title = {Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 12 09}, pages = {7173}, abstract = {

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are~correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6\% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

}, keywords = {Amino Acid Transport System y+, Cohort Studies, CpG Islands, DNA Methylation, Epigenome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Transport Proteins, Facilitative, Gout, Humans, Male, Uric Acid}, issn = {2041-1723}, doi = {10.1038/s41467-021-27198-4}, author = {Tin, Adrienne and Schlosser, Pascal and Matias-Garcia, Pamela R and Thio, Chris H L and Joehanes, Roby and Liu, Hongbo and Yu, Zhi and Weihs, Antoine and Hoppmann, Anselm and Grundner-Culemann, Franziska and Min, Josine L and Kuhns, Victoria L Halperin and Adeyemo, Adebowale A and Agyemang, Charles and Arnl{\"o}v, Johan and Aziz, Nasir A and Baccarelli, Andrea and Bochud, Murielle and Brenner, Hermann and Bressler, Jan and Breteler, Monique M B and Carmeli, Cristian and Chaker, Layal and Coresh, Josef and Corre, Tanguy and Correa, Adolfo and Cox, Simon R and Delgado, Graciela E and Eckardt, Kai-Uwe and Ekici, Arif B and Endlich, Karlhans and Floyd, James S and Fraszczyk, Eliza and Gao, Xu and G{\`a}o, Xin and Gelber, Allan C and Ghanbari, Mohsen and Ghasemi, Sahar and Gieger, Christian and Greenland, Philip and Grove, Megan L and Harris, Sarah E and Hemani, Gibran and Henneman, Peter and Herder, Christian and Horvath, Steve and Hou, Lifang and Hurme, Mikko A and Hwang, Shih-Jen and Kardia, Sharon L R and Kasela, Silva and Kleber, Marcus E and Koenig, Wolfgang and Kooner, Jaspal S and Kronenberg, Florian and Kuhnel, Brigitte and Ladd-Acosta, Christine and Lehtim{\"a}ki, Terho and Lind, Lars and Liu, Dan and Lloyd-Jones, Donald M and Lorkowski, Stefan and Lu, Ake T and Marioni, Riccardo E and M{\"a}rz, Winfried and McCartney, Daniel L and Meeks, Karlijn A C and Milani, Lili and Mishra, Pashupati P and Nauck, Matthias and Nowak, Christoph and Peters, Annette and Prokisch, Holger and Psaty, Bruce M and Raitakari, Olli T and Ratliff, Scott M and Reiner, Alex P and Sch{\"o}ttker, Ben and Schwartz, Joel and Sedaghat, Sanaz and Smith, Jennifer A and Sotoodehnia, Nona and Stocker, Hannah R and Stringhini, Silvia and Sundstr{\"o}m, Johan and Swenson, Brenton R and van Meurs, Joyce B J and van Vliet-Ostaptchouk, Jana V and Venema, Andrea and V{\"o}lker, Uwe and Winkelmann, Juliane and Wolffenbuttel, Bruce H R and Zhao, Wei and Zheng, Yinan and Loh, Marie and Snieder, Harold and Waldenberger, Melanie and Levy, Daniel and Akilesh, Shreeram and Woodward, Owen M and Susztak, Katalin and Teumer, Alexander and K{\"o}ttgen, Anna} }