Objective Previous studies have suggested an association between gout susceptibility and common dysfunctional variants in ATP-binding cassette transporter subfamily G member 2/breast cancer resistance protein (ABCG2/BCRP), including rs72552713 (Q126X) and rs2231142 (Q141K). However, the association of rare ABCG2 variants with gout is unknown. Therefore, we investigated the effects of rare ABCG2 variants on gout susceptibility in this study.
Methods We sequenced the exons of ABCG2 in 480 patients with gout and 480 healthy controls (Japanese males). We also performed functional analyses of non-synonymous variants of ABCG2 and analysed the correlation between urate transport function and scores from the protein prediction algorithms (Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping v2 (PolyPhen-2)). Stratified association analyses and multivariate logistic regression analysis were performed to evaluate the effects of rare and common ABCG2 variants on gout susceptibility.
Results We identified 3 common and 19 rare non-synonymous variants of ABCG2. SIFT scores were significantly correlated with the urate transport function, although some ABCG2 variants showed inconsistent scores. When the effects of common variants were removed by stratified association analysis, the rare variants of ABCG2 were associated with a significantly increased risk of gout (OR=3.2, p=6.4×10−3). Multivariate logistic regression analysis revealed that the size effect of these rare ABCG2 variants (OR=2.7, p=3.0×10−3) was similar to that of the common variants, Q126X (OR=3.4, p=3.2×10−6) and Q141K (OR=2.3, p=2.7×10−16).
Conclusions This study revealed that multiple common and rare variants of ABCG2 are independently associated with gout. These results could support both the ‘Common Disease, Common Variant’ and ‘Common Disease, Multiple Rare Variant’ hypotheses for the association between ABCG2 and gout susceptibility.
- gene polymorphism
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Contributor THigashino, TT, HNakaoka and YToyoda contributed equally.
Contributors THi, TT, HNakao, KH, NS and HMa conceived and designed this study. BS and KY assisted with research design. KW, RO and HO collected samples and analysed clinical data. THi, HNakao, SS, MS, MK, AN, AA, YTa, YK, KY, KH, II, NS and HMa performed genetic analysis. TT, YTo, HMi and YI performed functional analysis. THi, HNakao, HNakas, TN and HMa performed statistical analyses. BS, KY, KH, THo, KI, HS, TRM and NS provided intellectual input and assisted with the preparation of the manuscript. THi, TT, HNakao, YTo and HMa wrote the manuscript. All authors have read and approved the final version of the manuscript.
Funding This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, including MEXT KAKENHI (Nos 25293145 and 15K15227), Grants-in-Aid for Scientific Research on Priority Areas (No 17015018) and Innovative Areas (Nos 221S0001 and 221S0002) and JSPS KAKENHI Grants (Nos 16H06277 and 16H06279), the Ministry of Health, Labour and Welfare of Japan, the Ministry of Defense of Japan, the Japan Society for the Promotion of Science, the Kawano Masanori Memorial Foundation for Promotion of Pediatrics, the Gout Research Foundation of Japan and the Health Research Council of NZ.
Competing interests TT, TN, KI, HS, NS and HMa have a patent pending based on the work reported in this paper.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.
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