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Serum urate gene associations with incident gout, measured in the Framingham Heart Study, are modified by renal disease and not by body mass index

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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.

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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.

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Correspondence to Jasvinder A. Singh.

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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.

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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

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