Association of a Gout Polygenic Risk Score with Disease Severity Phenotypes Amongst Caucasian Gout Patients in Three Independent Cohorts

Nicholas Sumpter¹, Tony Merriman ², Richard Reynolds ³, Abhishek Abhishek ⁴, Mariano Andrés ⁵, Nicola Dalbeth ⁶, Michael Doherty ⁴, Lennart Jacobsson ⁷, Matthijs Janssen ⁸, Tim Jansen ⁹, Leo Joosten ¹⁰, Meliha Kapetanovic ¹¹, Frédéric Lioté ¹², Hirotaka Matsuo ¹³, Geraldine McCarthy ¹⁴, Fernando Perez-Ruiz ¹⁵, Philip Riches ¹⁶, Pascal Richette ¹⁷, Edward Roddy ¹⁸, Blanka Stiburkova ¹⁹, Alex So ²⁰, Lisa Stamp ²¹, Anne-Kathrin Tausche ²², Rosa Torres-Jimenez ²³ and Till Uhlig ²⁴, ¹University of Otago, Birmingham, ²University of Otago, Birmingham, AL, ³University of Alabama at Birmingham, Birmingham, ⁴The University of Nottingham, Nottingham, United Kingdom, ⁵Hospital General Universitario de Alicante, Alicante, Spain, ⁶University of Auckland, Auckland, New Zealand, ⁷Dept of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden,, Gothenburg, Sweden, ⁸Rijnstate Hospital, Arnhem, Netherlands, ⁹Viecuri MC, Venlo, Netherlands, ¹⁰Department of Internal Medicine and Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, Netherlands, ¹¹Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Section of Rheumatology, Lund and Malmö, Sweden, Lund, Sweden, ¹²Rheumatology Department, Lariboisiere Hospital, AP-HP, Paris, France, Paris, France, ¹³National Defense Medical College, Tokorozawa, Japan, ¹⁴University College Dublin, Dublin, Ireland, ¹⁵Hospital de Cruces, Vizcaya, Spain, ¹⁶The University of Edinburgh, Edinburgh, United Kingdom, ¹⁷Department of Rheumatology, AP-HP Lariboisiere Hospital, Paris, France, ¹⁸Research Institute for Primary Care and Health Sciences and Keele Clinical Trials Unit, Keele, United Kingdom, ¹⁹Institute of Rheumatology; Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic, Prague, Czech Republic, ²⁰Universite de Lausanne, Lausanne, Switzerland, ²¹University of Otago, Christchurch, Christchurch, Canterbury, New Zealand, ²²Universitatsklinikum Dresden, Dresden, Germany, ²³Instituto de Investigación Sanitaria del Hospital Universitario La Paz, Madrid, Spain, ²⁴Diakonhjemmet Hospital, Dept. of Rheumatology / University of Oslo, Faculty of Medicine, Oslo, Norway

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: genetics and tophaceous gout, gout

Session Information

Date: Tuesday, November 12, 2019

Title: 5T112: Metabolic & Crystal Arthropathies II: Genetics & Physiology (2834–2839)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose:

This study aimed to determine whether a polygenic risk score (PRS) based on gout-associated genetic variants is associated with gout disease severity phenotypes such as age at onset, presence of tophi and flare frequency.

Methods: A genome wide association study (GWAS) for gout was performed on all genotyped SNPs (single nucleotide polymorphisms) in approximately 500,000 individuals from the UK Biobank cohort. All genome-wide significant SNPs (P < 5 x 10^-8; total 129) were extracted and manually grouped into loci if they were within 500 kb of eachother. This resulted in a total of 12 loci, from which the most significant SNP of each locus was selected for analysis. Three cohorts of gout patients were involved in this analysis: the New Zealand Gout Study Caucasian cohort (NZ Gout; 782 males, 164 females), the Ardea cohort (1121 males, 57 females) and the EuroGout cohort (1114 males, 143 females). A PRS was calculated for each individual based on their genotypes at the 12 SNPs of interest and weighted by the effect size (odds ratio) of each SNP as determined by GWAS. The PRS was modelled against each of the three phenotypes of interest using linear and logistic models, adjusted by age at collection, sex and BMI (for all three cohorts) and the top 10 principle components (for the NZ Gout cohort). The adjusted models were meta-analysed.

Results: The PRS was distributed similarly for all three cohorts and ranged from 4.73 to 28.49. It showed a highly significant positive association with gout status in the NZ Gout study cohort (OR = 1.21 (95%-CI: 1.16 to 1.26), P = < 2E-16; performed using matched non-gout controls from the NZ population). Meta-analysis of the three cohorts identified a statistically significant negative association between the PRS and the age at onset phenotype with each PRS unit increase associated with a 0.43 year decrease in age at onset (95%-CI: -0.61 to -0.25, P < 0.0001). Presence of tophi was also found to be statistically significantly associated with increasing PRS in the three cohorts (OR = 1.059 (95%-CI: 1.03 to 1.09), P < 0.0001). However, when adjusting for disease duration, the strength of the association was reduced (OR = 1.031 (95%CI: 1.00 to 1.062), P = 0.046). The flare frequency phenotype did not show significant association with the PRS in any cohort, or under meta-analysis (Beta = 0.022 (95%-CI: -0.063 to 0.107), P = 0.61).

Conclusion: A polygenic risk score may be useful for predicting the severity of gout for severity phenotypes that are non-confounded, such as age at onset. Earlier age at onset results in a longer disease duration, which in turn may be causally associated with increased risk of tophi, and those with tophi may experience significantly more gout flares per year. As the PRS can aid in prediction of age of onset, it may be possible to effectively predict and manage those that are more likely to experience severe gout. As GWAS become larger, more gout associated loci will likely be identified, thus enabling improvement of the current PRS and likely improving prediction for severe gout phenotypes.

Disclosure: N. Sumpter, None; T. Merriman, Ardea Biosciences, 2, 5, AstraZeneca, 2, 5, Ironwood Pharmaceuticals, 2; R. Reynolds, None; A. Abhishek, None; M. Andrés, None; N. Dalbeth, Abbvie, 5, 8, 9, Amgen, 2, AMGEN, 2, AstraZeneca, 2, 5, 8, 9, Dyve, 5, 8, 9, Dyve BioSciences, 5, Hengrui, 5, 8, 9, Horiaon, 5, 8, Horizon, 5, 8, 9, Janssen, 5, 8, 9, Kowa, 5, 8, 9, Pfizer, 5, 8, 9; M. Doherty, None; L. Jacobsson, None; M. Janssen, None; T. Jansen, AbbVie, Celgene Corporation, 5, Grunenthal, Sobi, 8, Olatec, Grunenthal, 2; L. Joosten, Olatec Therapeutics LLC; M. Kapetanovic, Abbvie, 5, Pfizer, 2; F. Lioté, None; H. Matsuo, None; G. McCarthy, None; F. Perez-Ruiz, None; P. Riches, None; P. Richette, Janssen, 8; E. Roddy, None; B. Stiburkova, None; A. So, None; L. Stamp, None; A. Tausche, None; R. Torres-Jimenez, None; T. Uhlig, None.

To cite this abstract in AMA style:

Sumpter N, Merriman T, Reynolds R, Abhishek A, Andrés M, Dalbeth N, Doherty M, Jacobsson L, Janssen M, Jansen T, Joosten L, Kapetanovic M, Lioté F, Matsuo H, McCarthy G, Perez-Ruiz F, Riches P, Richette P, Roddy E, Stiburkova B, So A, Stamp L, Tausche A, Torres-Jimenez R, Uhlig T. Association of a Gout Polygenic Risk Score with Disease Severity Phenotypes Amongst Caucasian Gout Patients in Three Independent Cohorts [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/association-of-a-gout-polygenic-risk-score-with-disease-severity-phenotypes-amongst-caucasian-gout-patients-in-three-independent-cohorts/. Accessed .

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