Abstract
We hypothesized that serum urate-associated SNPs, individually or collectively, interact with BMI and renal disease to contribute to risk of incident gout. We measured the incidence of gout and associated comorbidities using the original and offspring cohorts of the Framingham Heart Study. We used direct and imputed genotypes for eight validated serum urate loci. We fit binomial regression models of gout incidence as a function of the covariates, age, type 2 diabetes, sex, and all main and interaction effects of the eight serum urate SNPs with BMI and renal disease. Models were also fit with a genetic risk score for serum urate levels which corresponds to the sum of risk alleles at the eight SNPs. Model covariates, age (P = 5.95E−06), sex (P = 2.46E−39), diabetes (P = 2.34E−07), BMI (P = 1.14E−11) and the SNPs, rs1967017 (P = 9.54E−03), rs13129697 (P = 4.34E−07), rs2199936 (P = 7.28E−03) and rs675209 (P = 4.84E−02) were all associated with incident gout. No BMI by SNP or BMI by serum urate genetic risk score interactions were statistically significant, but renal disease by rs1106766 was statistically significant (P = 6.12E−03). We demonstrated that minor alleles of rs1106766 (intergenic, INHBC) were negatively associated with the risk of incident gout in subjects without renal disease, but not for individuals with renal disease. These analyses demonstrate that a significant component of the risk of gout may involve complex interplay between genes and environment.
Similar content being viewed by others
References
Arromdee E, Michet CJ, Crowson CS et al (2002) Epidemiology of gout: is the incidence rising? J Rheumatol 29:2403–2406
Lawrence RC, Felson DT, Helmick CG et al (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 58:26–35
Roddy E, Choi HK (2014) Epidemiology of gout. Rheum Dis Clin N Am 40:155–175
Yang Q, Köttgen A, Dehghan A et al (2010) Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet 3:523–530
Köttgen A, Albrecht E, Teumer A et al (2013) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 45:145–154
McAdams-DeMarco MA, Maynard JW, Baer AN et al (2012) Hypertension and the risk of incident gout in a population-based study: the atherosclerosis risk in communities cohort. J Clin Hypertens 14:675–679
McAdams DeMarco MA, Maynard JW, Baer AN et al (2012) Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the Atherosclerosis Risk in Communities cohort study. Arthritis Rheum 64:121–129
McAdams-DeMarco MA, Maynard JW, Baer AN et al (2013) A urate gene-by-diuretic interaction and gout risk in participants with hypertension: results from the ARIC study. Ann Rheum Dis 72:701–706
Bao Y, Curhan G, Merriman T et al (2015) Lack of gene–diuretic interactions on the risk of incident gout: the Nurses’ Health Study and Health Professionals Follow-up Study. Ann Rheum Dis 74:1394–1398
Aschard H, Lutz S, Maus B et al (2012) Challenges and opportunities in genome-wide environmental interaction (GWEI) studies. Hum Genet 131:1591–1613
Hunter DJ (2005) Gene–environment interactions in human diseases. Nat Rev Genet 6:287–298
Choi HK, Atkinson K, Karlson EW et al (2004) Alcohol intake and risk of incident gout in men: a prospective study. Lancet 363:1277–1281
Choi HK, Atkinson K, Karlson EW et al (2004) Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 350:1093–1103
Choi HK, Ford ES, Li C et al (2007) Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 57:109–115
Dawber TR, Meadows GF, Moore FEJ (1951) Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health Nations Health 41:279–286
Wang W, Bhole VM, Krishnan E (2015) Chronic kidney disease as a risk factor for incident gout among men and women: retrospective cohort study using data from the Framingham Heart Study. BMJ Open 5:e006843
Wang W, Krishnan E (2015) Cigarette smoking is associated with a reduction in the risk of incident gout: results from the Framingham Heart Study original cohort. Rheumatology 54:91–95
Rasheed H, Phipps-Green A, Topless R et al (2013) Association of the lipoprotein receptor-related protein 2 gene with gout and non-additive interaction with alcohol consumption. Arthritis Res Ther 15:R177
Krishnan E (2012) Gout and the risk for incident heart failure and systolic dysfunction. BMJ Open 2:e000282
Howie B, Marchini J, Stephens M (2011) Genotype imputation with thousands of genomes G3(1):457–470
Marchini J, Howie B (2010) Genotype imputation for genome-wide association studies. Nat Rev Genet 11:499–511
R Development Core Team (2009) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Phipps-Green AJ, Merriman ME, Topless R et al (2014) Twenty-eight loci that influence serum urate levels: analysis of association with gout. Ann Rheum Dis. doi:10.1136/annrheumdis-2014-205877
Chasman DI, Fuchsberger C, Pattaro C et al (2012) Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. Hum Mol Genet 21:5329–5343
Hughes K, Flynn T, de Zoysa J et al (2014) Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function. Kidney Int 85:344–351
Speliotes EK, Willer CJ, Berndt SI et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–948
Grant support
This study was supported by K01 AR060848 (R.J.R.) and P30 DK056336 (D.B.A., A.I.V.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Y.C.K. was supported by NIH grant K01 DK095032. A.I.V. was supported by R01 DK062148. J.A.S. is supported by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics (AHRQ CERTs) U19 HS021110, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) P50 AR060772 and U34 AR062891, National Institute on Aging (NIA) U01 AG018947, National Cancer Institute (NCI) U10 CA149950, the resources and the use of facilities at the VA Medical Center at Birmingham, Alabama and research contract CE-1304-6631 from the Patient Centered Outcomes Research Institute (PCORI). The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
J.A.S. has received research grants from Takeda and Savient and consultant fees from Savient, Takeda, Regeneron and Allergan. J.A.S. is a member of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; a member of the American College of Rheumatology’s Guidelines Subcommittee of the Quality of Care Committee; and a member of the Veterans Affairs Rheumatology Field Advisory Committee. Dr. Allison has received grants, donations, or consulting fees from Pfizer, Arena and Eisai pharmaceuticals.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Reynolds, R.J., Vazquez, A.I., Srinivasasainagendra, V. et al. Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index. Rheumatol Int 36, 263–270 (2016). https://doi.org/10.1007/s00296-015-3364-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00296-015-3364-4