THU0003 Comprehensive evaluation of the effects of rare and common exonic abcg2 variants on gout susceptibility

Background Gout is the most common form of inflammatory arthritis and is caused by hyperuricemia. Many previous studies have indicated that common dysfunctional variants of the gene encoding ATP-binding cassette transporter subfamily G member 2/breast cancer resistance protein (ABCG2/BCRP) increase the risk of gout and hyperuricemia. In addition, we recently showed that rare non-synonymous variants are also risk factors for gout. However, we have not evaluated the effects of synonymous and splice-site variants of ABCG2. Thus, to estimate the risk of genetic variants of ABCG2 more comprehensively, we analysed the association between all exonic variants and gout susceptibility. Objectives The main purpose of this study was to perform comprehensive in silico evaluation of the effects of all types of rare and common exonic ABCG2 variants on gout susceptibility in Japanese population. Methods We previously sequenced all the exons of ABCG2 in 480 patients with gout and 480 healthy controls (Japanese males) and performed functional analyses of non-synonymous variants. In this present study, we analysed the correlation between urate transport function and scaled C-score of CADDv1.3 (CADD score) of non-synonymous variants. We additionally performed Receiver Operating Characteristic (ROC) curve analysis and selected variants with altered function of more than 50% compared to wild-type ABCG2. Stratified association analyses and multivariate logistic regression analysis were performed to evaluate the effects of selected rare and common ABCG2 variants on gout susceptibility. Results We identified 4 common and 26 rare exonic or closely situated intronic variants of ABCG2. CADD scores showed significant correlation with the results of functional analyses on urate transport (p=0.014, r=−0.539). ROC curve analysis showed an area under the curve (AUC) of 0.775. The optimal cutoff value of CADD score was 15 for classifying variants with altered function of more than 50% compared to wild-type ABCG2 (sensitivity=0.88, specificity=0.67). Therefore, we selected variants with a CADD score greater than 15 for downstream analyses. All intronic or synonymous variants had low CADD scores and thus were removed. Multivariate logistic regression analysis showed that the rare variants of ABCG2 were associated with a significantly increased risk of gout and the size effect of these rare variants (odds ratio [OR]=2.7, p=0.012) was similar to that of the common variants, Q126X (OR=3.3, p=4.8×10–6) and Q141K (OR=2.3, p=8.6×10–16). Conclusions This study confirmed that both common and rare variants in ABCG2 increase gout susceptibility. Furthermore, our in silico analyses suggest that synonymous and splice-site variants of ABCG2 may not play a key role in the pathogenesis of gout. References [1] T. Higashino, et al. Multiple common and rare variants of ABCG2 cause gout. RMD Open, 2017;3:e000464. [2] M. Kircher, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014:46(3):310–5. Acknowledgements We would like to thank all the participants and the members of Japan Multi-Institutional Collaborative Cohort Study Shizuoka Field for their contribution. Disclosure of Interest None declared