Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population
Science Translational Medicine • 4 Nov 2009 • Vol 1, Issue 5 • p. 5ra11 • DOI: 10.1126/scitranslmed.3000237
Abstract
Gout, the “Disease of Kings” as it is often known, is a painful medical condition characterized by sharp acute pain in bone joints, due to the high deposition of uric acid crystals from the blood serum into the surrounding cartilage. It affects approximately 1% of the U.S. population and remains a significant public health concern. The prevalence of gout is much higher in certain Asian ethnic groups, and is also reportedly rising in African Americans. Current medical treatments are aimed at ameliorating pain severity, but as the underlying genetic etiology of the disease unfolds, new targets for future therapies are likely to be found.
Although genome-wide association studies (GWAS) have enabled the calculation of risk predispositions for a wide variety of complex diseases, the relation of gene function to the causality of disease-related mutations has remained largely unclear. A recent U.S. population–based study supported an association between urate levels and gout in individuals carrying variants in a multifunctional transporter gene, ABCG2. This study identified Q141K as a high-risk variant in nearly 10% of gout cases in Caucasians.
Now, a team led by Hirotaka Matsuo report that in a Japanese population, another risk variant in ABCG2, namely the Q126X nonfunctional mutation, confers an even higher risk associated with an increase in uric acid deposition in the blood and may cause gout in Asians. Because this gene is responsible for giving rise to a protein that transports harmful waste products and metabolites out of the kidney and gut, they extensively validate the biological activity of ABCG2 using functional assays in vitro that effectively recapitulate human data obtained from Japanese individuals afflicted with the disease. These findings lend weight to previously reported GWAS; moreover, these newly identified specific high-risk variants that block urate secretion may serve as potential intervention points for quelling the disease.
Abstract
Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.
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Supplementary Material
Summary
Materials and Methods
Fig. S1. Flowchart for molecular-function-based clinicogenetic analysis of gout with ABCG2 polymorphic variants.
Fig. S2. Genomic structure and mutation sites of the human ABCG2 gene.
Fig. S3. Results of sequence analysis of ABCG2 gene.
Fig. S4. Western blot analysis of wild-type and mutated ABCG2.
Fig. S5. Proposed model of renal and gut urate excretion.
Table S1. Primer pairs used for mutation analysis of the human ABCG2 gene.
Table S2. Association of Q141K in ABCG2 with clinical parameters.
References
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Information & Authors
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Published In
Science Translational Medicine
Volume 1 | Issue 5
November 2009
November 2009
Copyright
Copyright © 2009, American Association for the Advancement of Science.
Submission history
Received: 29 June 2009
Accepted: 16 October 2009
Acknowledgments
Acknowledgments: We thank all of the patients and healthy volunteers involved in this study; M. Nudejima, K. Nakanishi, T. Tamatsukuri, A. Kudo, T. Iwamoto, M. Miyazawa, J. Inoue, M. Watanabe, M. Wakai, Y. Utsumi, Y. Kitamura, Y. Kawamura, R. Kinoshita, and A. Fujii for genetic analysis; K. Matsumura and S. Matsuyama for technical support; T. Nakazono, H. Itosu, T. Oda, and Y. Kikuchi for patient analysis; M. Yamashiro, K. Takahashi, H. Nakashima, K. Ishii, A. Enomoto, T. Shimizu, T. Itoh, H. Sato, M. Emi, S. Suzuki, Y. Kobayashi, and J. Fukuda for helpful discussion; and D. E. Nadziejka for technical editing.
Funding: Ministry of Defense of Japan (H.M., K.K., Y.S., and N.S.); Ministry of Education, Science, and Culture of Japan (Scientific Research on Priority Areas, Transportsome; T.T., K. Ito, Y. Kanai, and H.S.); Japan Society for the Promotion of Science (K. Ichida); Nakabayashi Trust for ALS Research; Kawano Masanori Memorial Foundation for Promotion of Pediatrics; Takeda Science Foundation (H.M.); and Gout Research Foundation of Japan (H.M. and K. Ichida).
Author contributions: H.M., T.T., K. Ichida, and T.N. designed the experiment; T.T., Y.I., K. Ito, Y. Kanai, and H.S. performed functional analysis; H.M., K. Ichida, J.N., H.D., S.W., M.F., Y.M., T.H., and N.S. performed patient analysis; H.M., K. Ichida, Y. Kusanagi, T.C., S.T., Y.T., Y.O., H.I., K. Niwa, K.K., and N.S. carried out genetic analysis; H.M., T.N., A.N., S.N., Y.S., and N.H. performed QTL analysis; H.M., K. Ichida, A.N., K.S., R.O., M.N., K. Nishio, A.H., K.W., Y.A., T.H., and N.H. collected samples of patients and normal controls and analyzed data of samples; T.N. performed statistical analysis; H.M. wrote the paper; H.M., T.T., A.N., and N.S. revised the paper.
Competing interests: The authors have a patent pending based on the work reported in this paper.
Accession numbers: The amino acid sequence of ABCG2 shown in Fig. 2A was obtained from GenBank (accession code NM_004827). This sequence is identical to that from the ABCG2 clone used in this study. OMIM accession code for gout-susceptibility locus GOUT1 (GOUT SUSCEPTIBILITY 1) on chromosome 4q is MIM 138900.
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