Advances in multidimensional risk factors and comorbidities of gout based on UK Biobank data

Abstract

Gout is an increasingly prevalent inflammatory arthritis that substantially affects quality of life and contributes to a growing public health burden. Understanding its complex network of risk factors is crucial for effective prevention and management. The emergence of large-scale cohorts, particularly the UK Biobank, has facilitated etiologic, genetic, and clinical research on gout and related urate phenotypes. By providing multidimensional lifestyle, clinical, and omics data, the UK Biobank serves as a powerful resource for dissecting the multifaceted nature of gout. Here, we provide a critical narrative review of UK Biobank-based gout research, focusing on multidimensional determinants, convergent and conflicting evidence, comorbidity networks, clinical implications, and methodological limitations and potential biases. This review aims to provide an evidence-based framework for informing gout prevention, comorbidity assessment, and future research.

Keywords

Gout / UK Biobank / risk factors / epidemiology

References

[1] Cross M,Culbreth GT.Global, regional, and national burden of gout, 1990-2020, and projections to 2050: a systematic analysis of the global burden of disease study 2021.Lancet Rheumatol2024;6:e507-17

[2] Abhishek A,Doherty M.Gout - a guide for the general and acute physicians.Clin Med2017;17:54-9

[3] Zhang W.Uric acid en route to gout. In: Makowski GS, Editor. Advances In Clinical Chemistry. Elsevier; 2023. pp. 209-75.

[4] Dalbeth N,Stamp LK.Gout.Lancet2016;388:2039-52

[5] Garg M,Matelska D.Disease prediction with multi-omics and biomarkers empowers case-control genetic discoveries in the UK Biobank.Nat Genet2024;56:1821-31

[6] Cox N.UK Biobank shares the promise of big data.Nature2018;562:194-5

[7] Cadzow M,Dalbeth N.Performance of gout definitions for genetic epidemiological studies: analysis of UK Biobank.Arthritis Res Ther2017;19:181 PMCID:PMC5551011

[8] Tin A,Halperin Kuhns VL.Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.Nat Genet2019;51:1459-74

[9] Narang RK,Cadzow M.Interactions between serum urate-associated genetic variants and sex on gout risk: analysis of the UK Biobank.Arthritis Res Ther2019;21:13 PMCID:PMC6327586

[10] Tai V,Gamble G.Do serum urate-associated genetic variants differentially contribute to gout risk according to body mass index? Analysis of the UK Biobank.Arthritis Rheumatol2020;72:1184-91

[11] Sandoval-Plata G,Abhishek A.Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank.Ann Rheum Dis2021;80:1220-6

[12] Major TJ,Matsuo H.A genome-wide association analysis reveals new pathogenic pathways in gout.Nat Genet2024;56:2392-406

[13] Tao Y,Pan Q.Genetic variants associated with gout identified through a genome-wide study in the UK biobank (N = 150 542).Hum Mol Genet2025;34:1951-63

[14] McCormick N,Yokose C.Assessing the causal relationships between insulin resistance and hyperuricemia and gout using bidirectional Mendelian randomization.Arthritis Rheumatol2021;73:2096-104 PMCID:PMC8568618

[15] Adams CD.Using multiple Mendelian randomization approaches and genetic correlations to understand obesity, urate, and gout.Sci Rep2021;11:17799 PMCID:PMC8423843

[16] Zhang Y,Dove A.Healthy lifestyle counteracts the risk effect of genetic factors on incident gout: a large population-based longitudinal study.BMC Med2022;20:138 PMCID:PMC9052486

[17] Wu Q,Ye Z.Sleep patterns, genetic susceptibility, and risk of new-onset gout: the UK Biobank prospective cohort study.J Psychosom Res2023;170:111381

[18] Lyu JQ,Wang JM.Consumption of total and specific alcoholic beverages and long-term risk of gout among men and women.JAMA Netw Open2024;7:e2430700 PMCID:PMC11358860

[19] Dai H,Wang Q.The effect of metformin on urate metabolism: findings from observational and Mendelian randomization analyses.Diabetes Obes Metab2024;26:242-50

[20] Liu M,Zhang Y.Associations of habitual glucosamine supplementation with incident gout: a large population based cohort study.Biol Sex Differ2022;13:52 PMCID:PMC9524004

[21] Li A,Zhou L.Long-term exposure to ambient air pollution and incident gout: a prospective cohort study in the UK Biobank.Environ Pollut2024;345:123540

[22] Liu W,Hua B.Association between combined exposure to ambient air pollutants, genetic risk, and incident gout risk: a prospective cohort study in the UK Biobank.Semin Arthritis Rheum2024;66:152445

[23] Jiang Y,Liu G,Peng M.Association between sex hormones and gout: an analysis of the UK Biobank cohort.Steroids2024;207:109422

[24] Joshi AD,Yokose C.Prediagnostic glycoprotein acetyl levels and incident and recurrent flare risk accounting for serum urate levels: a population-based, prospective study and Mendelian randomization analysis.Arthritis Rheumatol2023;75:1648-57

[25] Agrawal M,Cunin P.TET2-mutant clonal hematopoiesis and risk of gout.Blood2022;140:1094-103

[26] Sandoval-Plata G,Chakravorty M,Abhishek A.Association between serum urate, gout and comorbidities: a case-control study using data from the UK Biobank.Rheumatology2021;60:3243-51

[27] Zhu J,Zhang H.The association of hyperuricemia and gout with the risk of cardiovascular diseases: a cohort and Mendelian randomization study in UK Biobank.Front Med2021;8:817150 PMCID:PMC8985123

[28] Narang RK,Topless R.Assessing the relationship between serum urate and urolithiasis using Mendelian randomization: an analysis of the UK Biobank.Am J Kidney Dis2021;78:210-8

[29] Topless RK,Stamp LK,Dalbeth N.Gout and the risk of COVID-19 diagnosis and death in the UK Biobank: a population-based study.Lancet Rheumatol2022;4:e274-81 PMCID:PMC8798088

[30] Kang Z,Zhu C.Impaired pulmonary function increases the risk of gout: evidence from a large cohort study in the UK Biobank.BMC Med2024;22:606 PMCID:PMC11686989

[31] Liu X,Song H.Metabolic dysfunction-associated fatty liver disease and the risk of gout: a UK Biobank prospective cohort study.Eur J Med Res2025;30:1027 PMCID:PMC12570524

[32] Boocock J,Okada Y.Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control.Hum Mol Genet2020;29:923-43

[33] Risk Score Task Force of the International Common Disease Alliance. Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps.Nat Med2021;27:1876-84

[34] Lewis ACF.Polygenic risk scores in the clinic: new perspectives needed on familiar ethical issues.Genome Med2021;13:14 PMCID:PMC7844961

[35] Karlsson T,Rask-Andersen M,Ek WE.Body mass index and the risk of rheumatic disease: linear and nonlinear Mendelian randomization analyses.Arthritis Rheumatol2023;75:2027-35

[36] Lin KC,Chou P.The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study.J Rheumatol2000;27:1501-5

[37] Bhole V,Rahman MM,Choi H.Epidemiology of gout in women: fifty-two-year followup of a prospective cohort.Arthritis Rheum2010;62:1069-76

[38] Panlu K,Huang L,Wen C.Associations between obesity and hyperuricemia combing Mendelian randomization with network pharmacology.Heliyon2024;10:e27074 PMCID:PMC10951504

[39] Li N,Han M.Biological aging and gout risk in hyperuricemia: a UK Biobank cohort study.Int J Surg2026;112:3541-52

[40] Sun Y,Li D.Association between frailty and gout in middle-aged and older adults: a nationwide cross-sectional and Mendelian randomization study.Medicine2025;104:e45794 PMCID:PMC12599745

[41] Lv Z,Zhang J.Associations between serum urate and telomere length and inflammation markers: evidence from UK Biobank cohort.Front Immunol2022;13:1065739 PMCID:PMC9797991

[42] Chuah MH,Topless RK.Interaction of genetic variation at ADH1B and MLXIPL with alcohol consumption for elevated serum urate level and gout among people of European ethnicity.Arthritis Res Ther2024;26:45 PMCID:PMC10851571

[43] Choi HK,Karlson EW,Curhan G.Alcohol intake and risk of incident gout in men: a prospective study.Lancet2004;363:1277-81

[44] Neogi T,Niu J,Hunter DJ.Alcohol quantity and type on risk of recurrent gout attacks: an internet-based case-crossover study.Am J Med2014;127:311-8 PMCID:PMC3991555

[45] Guo H,Peng H.Dose-response relationships of tea and coffee consumption with gout: a prospective cohort study in the UK Biobank.Rheumatology2023;62:3043-50

[46] Choi HK,Curhan G.Coffee consumption and risk of incident gout in men: a prospective study.Arthritis Rheum2007;56:2049-55

[47] Choi HK.Coffee consumption and risk of incident gout in women: the nurses’ health study.Am J Clin Nutr2010;92:922-7 PMCID:PMC2937590

[48] Hutton J,Major TJ.Mediation analysis to understand genetic relationships between habitual coffee intake and gout.Arthritis Res Ther2018;20:135 PMCID:PMC6034252

[49] Nicolopoulos K,Zhou A.Association between habitual coffee consumption and multiple disease outcomes: a Mendelian randomisation phenome-wide association study in the UK Biobank.Clin Nutr2020;39:3467-76

[50] Shirai Y,Kawamura Y.Coffee consumption reduces gout risk independently of serum uric acid levels: Mendelian randomization analyses across ancestry populations.ACR Open Rheumatol2022;4:534-9 PMCID:PMC9190218

[51] Qin T,Yao Y,Xu B.Coffee intake reduced gout risk by decreasing urate and urea while increasing SHBG levels in plasma: a mediation Mendelian randomization study.Clin Rheumatol2024;43:1735-43

[52] Yu Y,Hu G,Yin Y.Effect of tea intake on genetic predisposition to gout and uric acid: a Mendelian randomization study.Front Endocrinol2023;14:1290731 PMCID:PMC10911082

[53] Zhang T,Chang Q.Ultraprocessed food consumption, genetic predisposition, and the risk of gout: the UK Biobank study.Rheumatology2024;63:165-73

[54] Hua B,Yang Y.Dietary carbohydrates, genetic susceptibility, and gout risk: a prospective cohort study in the UK.Nutrients2024;16:2883 PMCID:PMC11397129

[55] Wang X,Zhang W.Empirical dietary index for lower urate concentrations and risk of gout: evidence from cohort studies.Am J Clin Nutr2025;122:793-802 PMCID:PMC12329690

[56] Major TJ,Dalbeth N.Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts.BMJ2018;363:k3951 PMCID:PMC6174725

[57] Topless RKG,Florez JC.The comparative effect of exposure to various risk factors on the risk of hyperuricaemia: diet has a weak causal effect.Arthritis Res Ther2021;23:75 PMCID:PMC7931603

[58] Tao HW,Jiang W.Lower plasma linoleic acids as a risk factor for gout: an integrated analysis of population-based cohort and genetic data.Food Funct2024;15:7567-76

[59] Chen L,Wu Q.Dietary polyunsaturated fatty acid and risk of gout: a cohort study integrating genetic predisposition and metabolomics.Eur J Epidemiol2025;40:427-39

[60] Wu Z,He H.Association of walking volume and intensity with incident gout: a population-based cohort study.Am J Epidemiol2025;194:2945-53

[61] Wang Q,Zhu B.Accelerometer-derived physical activity patterns and risk of incident gout: a prospective cohort study of 97,387 UK Biobank participants.Arthritis Res Ther2025;28:38 PMCID:PMC12896187

[62] Wu Z,Wang Y.Genetic susceptibility, walking activity and the risk of incident gout.Rheumatology2026;65:keaf690

[63] Guan Y,Meng L.Genetically predicted physical activity is associated with lower serum urate concentrations.Genes Genomics2022;44:843-53

[64] Yang T,Zhang X,Feng S.The impact of different intensities of physical activity on serum urate and gout: a Mendelian randomization study.Metabolites2024;14:66 PMCID:PMC10819057

[65] Zou C,Huang W.Linear and non-linear Mendelian randomization analyses of sex-specific associations between sleep duration and hyperuricemia.Front Nutr2022;9:920791 PMCID:PMC9632753

[66] Gee Teng G,Yuan JM.Cigarette smoking and the risk of incident gout in a prospective cohort study.Arthritis Care Res2016;68:1135-42 PMCID:PMC5515666

[67] Burke BT,Law A.Gout in older adults: the atherosclerosis risk in communities study.J Gerontol A Biol Sci Med Sci2016;71:536-42 PMCID:PMC5014186

[68] Narang RK,Phipps-Green AJ.Do serum urate-associated genetic variants influence gout risk in people taking diuretics? Analysis of the UK Biobank.J Rheumatol2020;47:1704-11

[69] Asiimwe IG,Sofat R,Pirmohamed M.Genetic determinants of thiazide-induced hyperuricemia, hyperglycemia, and urinary electrolyte disturbances - a genome-wide evaluation of the UK Biobank.Clin Pharmacol Ther2024;115:1408-17

[70] McAdams-DeMarco MA,Baer AN,Kottgen A.A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study.Ann Rheum Dis2013;72:701-6 PMCID:PMC4565188

[71] Marrugo J,Paudel ML.Gout risk in adults with pre-diabetes initiating metformin.Ann Rheum Dis2024;83:1368-74 PMCID:PMC11442121

[72] Zhao SS,Karhunen V,Gill D.Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomisation study.Semin Arthritis Rheum2022;56:152058

[73] McCormick N,Lu N.Sodium-glucose cotransporter-2 inhibitors vs sulfonylureas for gout prevention among patients with type 2 diabetes receiving metformin.JAMA Intern Med2024;184:650-60 PMCID:PMC11019449

[74] Preston FG,Riley DR.SGLT2 inhibitors, but not GLP-1 receptor agonists, reduce incidence of gout in people living with type 2 diabetes across the therapeutic spectrum.Clin Ther2024;46:835-40

[75] Tang YX,Qian ZM.Association between ambient air pollution and hyperuricemia in traffic police officers in China: a cohort study.Int J Environ Health Res2021;31:54-62

[76] Duan L,Cao Y.Exposure to ambient air pollutants is associated with an increased incidence of hyperuricemia: a longitudinal cohort study among Chinese government employees.Environ Res2023;235:116631

[77] Tang YX,Xu YJ.Exposure to ambient particulate matter and hyperuricemia: An eight-year prospective cohort study on male traffic officers in China.Ecotoxicol Environ Saf2023;249:114354

[78] Wei S,Ren S,Fang X.Associations of domestic hard water metrics with the risk of gout incidence and recurrence.PLoS One2025;20:e0326052 PMCID:PMC12258571

[79] Schwartz BF,Bruce JE,Stoller ML.Calcium nephrolithiasis: effect of water hardness on urinary electrolytes.Urology2002;60:23-7

[80] Yuan S,Sun J.Genetically predicted sex hormone levels and health outcomes: phenome-wide Mendelian randomization investigation.Int J Epidemiol2022;51:1931-42 PMCID:PMC9749729

[81] McCormick N,Yokose C.Prediagnostic amino acid metabolites and risk of gout, accounting for serum urate: prospective cohort study and Mendelian randomization.Arthritis Care Res2024;76:1666-74 PMCID:PMC11711019

[82] Sun M,Reynolds RJ.Untangling the complex relationships between incident gout risk, serum urate, and its comorbidities.Arthritis Res Ther2018;20:90 PMCID:PMC5932762

[83] Li X,Spiliopoulou A.MR-PheWAS: exploring the causal effect of SUA level on multiple disease outcomes by using genetic instruments in UK Biobank.Ann Rheum Dis2018;77:1039-47 PMCID:PMC6029646

[84] Li X,He Y.Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: a phenome-wide Mendelian randomization study.PLoS Med2019;16:e1002937 PMCID:PMC6799886

[85] Gill D,Burgess S.Urate, blood pressure, and cardiovascular disease: evidence from Mendelian randomization and meta-analysis of clinical trials.Hypertension2021;77:383-92 PMCID:PMC7803439

[86] Jung SM,Lee SN.The impact of lifestyle on cardiovascular risk in patients with gout: a population-based cohort study.Eur Heart J Qual Care Clin Outcomes2025;11:397-405

[87] Moon KW,Do H.Cardiovascular risk according to genetic predisposition to gout, lifestyle and metabolic health across prospective European and Korean cohorts.RMD Open2024;10:e004552 PMCID:PMC11474875

[88] Jordan DM,Verbanck M.No causal effects of serum urate levels on the risk of chronic kidney disease: a Mendelian randomization study.PLoS Med2019;16:e1002725 PMCID:PMC6333326

[89] Liu S,Cai Y.Gout drives metabolic dysfunction-associated steatotic liver disease through gut microbiota and inflammatory mediators.Sci Rep2025;15:9395 PMCID:PMC11920238

[90] Zhang T,Shen Z.Joint association of serum urate and healthy diet with chronic obstructive pulmonary disease incidence: results from the UK Biobank study.Food Funct2024;15:4642-51

[91] Topless RK,Leask M.Gout, rheumatoid arthritis, and the risk of death related to coronavirus disease 2019: an analysis of the UK Biobank.ACR Open Rheumatol2021;3:333-40 PMCID:PMC8126763

[92] Li Y,Xu Z.J-shaped associations of serum urate with all-cause and cause-specific mortality in diabetes: mediation by kidney function.Acta Diabetol2026;63:507-19

[93] Wu C,Liu L.Association of metabolic syndrome and hyperuricemia with mortality in patients with chronic kidney disease: a UK biobank study.BMC Nephrol2025;26:696 PMCID:PMC12706888

[94] Jiang Z,Wu S.Serum uric acid levels associated with outcomes of neurodegenerative disorders and brain health: findings from the UK Biobank.J Nutr Health Aging2024;28:100319 PMCID:PMC12880037

[95] Shi W,Wei S.Assessing the impact of gout on cancer risk and the role of healthy lifestyles.Front Oncol2025;15:1557175 PMCID:PMC12066266

[96] Horsfall LJ,Nazareth I.Serum urate and lung cancer: a cohort study and Mendelian randomization using UK Biobank.Respir Res2021;22:179 PMCID:PMC8210393

[97] Zhou Y,Hu H,Shen N.Serum urate levels and colorectal cancer risk: a prospective cohort study in of the UK biobank and a Mendelian randomization analysis.Discov Oncol2025;16:2063 PMCID:PMC12595151

[98] Lee YH.Uric acid level, gout and bone mineral density: a Mendelian randomization study.Eur J Clin Invest2019;49:e13156

[99] Yao Y,Ma M.Evaluate the effects of serum urate level on bone mineral density: a genome-wide gene-environment interaction analysis in UK Biobank cohort.Endocrine2021;73:702-11

[100] Gao Q,Zhang J.Causal association between erectile dysfunction with urate levels and gout: a two-sample Mendelian randomization study.Arch Esp Urol2025;78:902-8

[101] Sudlow C,Allen N.UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med2015;12:e1001779 PMCID:PMC4380465

[102] Fry A,Sudlow C.Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population.Am J Epidemiol2017;186:1026-34 PMCID:PMC5860371

[103] van Alten S,Faul J,Marees AT.Reweighting UK Biobank corrects for pervasive selection bias due to volunteering.Int J Epidemiol2024;53 PMCID:PMC11076923

[104] Cho C,Kim DS.Large-scale cross-ancestry genome-wide meta-analysis of serum urate.Nat Commun2024;15:3441 PMCID:PMC11043400

[105] Köttgen A,Teumer A.Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.Nat Genet2013;45:145-54

[106] Vitart V,Hayward C.SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.Nat Genet2008;40:437-42

[107] Döring A,Mehta D.SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.Nat Genet2008;40:430-6

[108] Chiba T,Kawamura Y.NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout.Arthritis Rheumatol2015;67:281-7

[109] Fujii W,Hirohama D.Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12.J Clin Invest2025;135 PMCID:PMC12077893

[110] Yin W,Huang W,Wang Y.Lifestyle factors and hyperuricemia risk: a prospective cohort study of 14,635 participants examining the protective role of daily stair climbing.Front Nutr2025;12:1635746 PMCID:PMC12364643

[111] Choi HK,Karlson EW.Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study.Arch Intern Med2005;165:742-8