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Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities

Abstract

Hypertension, obesity, chronic kidney disease and type 2 diabetes are comorbidities that have very high prevalence among persons with hyperuricemia (serum urate > 6.8 mg/dL) and gout. Here we use multivariate genetic models to test the hypothesis that the co-association of traits representing hyperuricemia and its comorbidities is genetically based. Using Bayesian whole-genome regression models, we estimated the genetic marker-based variance and the covariance between serum urate, serum creatinine, systolic blood pressure (SBP), blood glucose and body mass index (BMI) from two independent family-based studies: The Framingham Heart Study-FHS and the Hypertension Genetic Epidemiology Network study-HyperGEN. The main genetic findings that replicated in both FHS and HyperGEN, were (1) creatinine was genetically correlated only with urate and (2) BMI was genetically correlated with urate, SBP, and glucose. The environmental covariance among the traits was generally highest for trait pairs involving BMI. The genetic overlap of traits representing the comorbidities of hyperuricemia and gout appears to cluster in two separate axes of genetic covariance. Because creatinine is genetically correlated with urate but not with metabolic traits, this suggests there is one genetic module of shared loci associated with hyperuricemia and chronic kidney disease. Another module of shared loci may account for the association of hyperuricemia and metabolic syndrome. This study provides a clear quantitative genetic basis for the clustering of comorbidities with hyperuricemia.

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Fig. 1: Marker-based heritability of five traits estimated using Bayesian whole genome regression from two studies.
Fig. 2: Genetic (Y-axis) and environmental (X-axis) correlation estimates from multi-trait model fit to the FHS and HyperGEN datasets.

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Acknowledgements

RJR, SLB, TRM, JAS, and AIV acknowledge support from P50 AR060772. RJR acknowledges support from K01 AR060848 and the Arthritis National Research Foundation. AIV acknowledges financial support from NIH grant 7-R01-DK-062148-10-S1, R01GM09992, and R01GM101219. The Hypertension Genetic Epidemiology Network (HyperGEN) Study is part of the NHLBI Family Blood Pressure Program. Collection of the data represented here was supported by grants U01 HL054472, U01 HL054473, U01 HL054495, and U01 HL054509. The HyperGEN: Genetics of Left Ventricular Hypertrophy Study was supported by NHLBI grant R01 HL055673. We gratefully acknowledge scientists conducting the HyperGEN and Framingham Heart Study for collecting, analyzing, and providing the genotypic and phenotypic data used in the present study, as well as the invaluable dedication of the HyperGEN and Framingham Heart Study participants. The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). 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-HL64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding for Affymetrix genotyping of the FHS Omni cohorts was provided by Intramural NHLBI funds from Andrew D. Johnson and Christopher J. O’Donnell.

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Correspondence to Richard J. Reynolds or Ana I. Vazquez.

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AIV has received consultant fees from University of Alabama at Birmingham and University of Texas, Austin. JAS has received consultant fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, Clinical Care options, Clearview healthcare partners, Putnam associates, Spherix, Practice Point communications, the National Institutes of Health and the American College of Rheumatology. JAS owns stock options in Amarin pharmaceuticals and Viking therapeutics. JAS is on the speaker’s bureau of Simply Speaking. JAS is a member of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 12 companies. JAS serves on the FDA Arthritis Advisory Committee. JAS is a member of the Veterans Affairs Rheumatology Field Advisory Committee. JAS is the editor and the Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. JAS previously served as a member of the following committees: member, the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC) and Quality of Care Committees, the Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and the co-chair of the ACR Criteria and Response Criteria subcommittee.

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Reynolds, R.J., Irvin, M.R., Bridges, S.L. et al. Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities. Eur J Hum Genet 29, 1438–1445 (2021). https://doi.org/10.1038/s41431-021-00830-z

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