Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: We have reported that ABCG2 has an important role in both renal and intestinal urate excretion and these common variants as rs72552713 (Q126X) and rs2231142 (Q141K) are risks for gout. Then, we revealed both rare and common non-synonymous ABCG2 variants are associated with gout susceptibility. In this study, we investigated the effects of rare and common ABCG2 variants including synonymous, non-synonymous and splice-site variants on gout.
Methods: We sequenced exons of ABCG2 in 480 patients with gout and 480 healthy controls (Japanese males). Additionally, functional analyses of non-synonymous variants of ABCG2 were performed. Then, the correlation between urate transport function and scaled C-score of CADDv1.3 (CADD score) was analyzed. Furthermore, we performed Receiver Operating Characteristic (ROC) curve analysis and made selections of variants with altered function of more than 50% compared to wild-type ABCG2. In order to assess the effects of common and rare variants on gout susceptibility, we conducted stratified association analyses and multivariate logistic regression analysis.
Results: We identified 5 common and 25 rare exonic or closely situated intronic variants of ABCG2. CADD scores demonstrated relationships with the urate transport function significantly (p=0.014, r=-0.539.) ROC curve analysis demonstrated an area under the curve (AUC) of 0.775. The appropriate cutoff value of CADD score was 15 when we classified variants with mutated function of more than 50% compared to wild-type ABCG2 (sensitivity=0.88, specificity=0.67.) Therefore, we carried out the downstream analyses of variants with a CADD score greater than 15. Both intronic and synonymous variants showed low CADD scores. Then we removed them on multivariate logistic regression analysis and revealed that rare variants of ABCG2 significantly increased gout risk and the size effect of these rare variants (odds ratio [OR]=2.7, p=0.012) was similar to that of common variants such as Q126X (OR=3.3, p=4.8×10-6) and Q141K (OR=2.3, p=8.6×10-16).
Conclusion: We confirmed that both common and rare variants of ABCG2 have independent effects on risk of gout. Our findings help to better understand both eCommon Disease, Common Variantf and eCommon disease, Multiple Rare Variantf hypotheses for the association between ABCG2 and gout susceptibility. In addition, our in silico analyses suggest that there are no important synonymous and splice-site variants of ABCG2 for the pathogenesis of gout.
To cite this abstract in AMA style:Matsuo H, Higashino T, Takada T, Nakaoka H, Toyoda Y, Stiburkova B, Nakashima H, Shimizu S, Kawaguchi M, Nakayama A, Aoki Y, Ishino M, Kawamura Y, Wakai K, Okada R, Hosoya T, Ichida K, Ooyama H, Suzuki H, Inoue I, Major TJ, Merriman TR, Shinomiya N. Comprehensive Association Analysis between Rare and Common ABCG2 Variants and Gout Susceptibility [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/comprehensive-association-analysis-between-rare-and-common-abcg2-variants-and-gout-susceptibility/. Accessed June 6, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/comprehensive-association-analysis-between-rare-and-common-abcg2-variants-and-gout-susceptibility/