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.

1st Faculty of Medicine Charles University and General University Hospital Prague Institute of Inherited Metabolic Disorders Prague Czech Republic

Department of Biochemistry University of Otago Dunedin New Zealand

Department of Bioinformatics and Genomics Graduate School of Medical Sciences Kanazawa University Ishikawa Japan

Department of Integrative Physiology and Bio Nano Medicine National Defense Medical College Tokorozawa Japan

Department of Medical Chemistry Kurume University School of Medicine Kurume Japan

Department of Pathophysiology and Therapy in Chronic Kidney Disease Jikei University School of Medicine Tokyo Japan

Department of Pathophysiology Tokyo University of Pharmacy and Life Sciences Tokyo Japan

Department of Pharmacy The University of Tokyo Hospital Faculty of Medicine The University of Tokyo Tokyo Japan

Department of Preventive Medicine and Public Health National Defense Medical College Tokorozawa Japan

Department of Preventive Medicine Nagoya University Graduate School of Medicine Nagoya Japan

Division of Human Genetics Department of Integrated Genetics National Institute of Genetics Mishima Japan

Division of Kidney and Hypertension Department of Internal Medicine Jikei University School of Medicine Tokyo Japan

Institute of Rheumatology Prague Czech Republic

Laboratory for Mathematics National Defense Medical College Tokorozawa Japan

Ryougoku East Gate Clinic Tokyo Japan

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Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout

Interaction of the p.Q141K Variant of the ABCG2 Gene with Clinical Data and Cytokine Levels in Primary Hyperuricemia and Gout

Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout

Functional Characterization of Clinically-Relevant Rare Variants in ABCG2 Identified in a Gout and Hyperuricemia Cohort

The impact of dysfunctional variants of ABCG2 on hyperuricemia and gout in pediatric-onset patients