Common dysfunctional variants in ABCG2 are a major cause of early-onset gout

Ichida, Kimiyoshi; Takada, Tappei; Nakayama, Akiyoshi; Nakashima, Hiroshi; Nakamura, Takahiro; Takada, Yuzo; Yamamoto, Ken; Inoue, Hiroki; Oikawa, Yuji; Naito, Mariko; Hishida, Asahi; Wakai, Kenji; Okada, Chisa; Shimizu, Seiko; Sakiyama, Masayuki; Chiba, Toshinori; Ogata, Hiroyasu; Niwa, Kazuki; Hosoyamada, Makoto; Mori, Atsuyoshi; Hamajima, Nobuyuki; Suzuki, Hiroshi; Kanai, Yoshikatsu; Sakurai, Yoshinori; Hosoya, Tatsuo; Shimizu, Toru; Shinomiya, Nariyoshi

doi:10.1038/srep02014

Cited by 110 publications

(93 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We and other groups [5][6][7][8][9] recently reported gout/ hyperuricaemia to have relatively strong genetic risk factors. More recently, and for the first time, we performed a GWAS with only clinically defined Japanese male gout cases in which 16 single nucleotide polymorphisms (SNPs) were replicated, and five gout-risk loci were identified including two novel loci (MYL2-CUX2 and CNIH-2).…”

Section: Introductionmentioning

confidence: 67%

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

et al. 2016

Self Cite

View full text Add to dashboard Cite

ObjectiveA genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.MethodsPutative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study.ResultsIn addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10−8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (pmeta=3.58×10−8).ConclusionsOur findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

show abstract

Section: Introductionmentioning

confidence: 67%

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…[6,7] In addition, ABCG2 has been identified as a high-capacity urate exporter that would mediate renal and/or extra-renal urate excretion, [6] and its dysfunction has an association with SUA levels and gout/hyperuricemia risk. [6,8] However, pathophysiologically important pathway(s) responsible for the ABCG2-mediated urate excretion were unknown. In the present study, we investigated how ABCG2 dysfunction affected the urate excretion pathways in mouse model.…”

Section: Introductionmentioning

confidence: 99%

ABCG2 Dysfunction Increases Serum Uric Acid by Decreased Intestinal Urate Excretion

Takada

Ichida

Matsuo

et al. 2014

Nucleosides, Nucleotides and Nucleic Acids

Self Cite

View full text Add to dashboard Cite

ATP-binding cassette transporter G2 (ABCG2), also known as breast cancer resistance protein (BCRP), is identified as a high-capacity urate exporter and its dysfunction has an association with serum uric acid (SUA) levels and gout/hyperuricemia risk. However, pathophysiologically important pathway(s) responsible for the ABCG2-mediated urate excretion were unknown. In this study, we investigated how ABCG2 dysfunction affected the urate excretion pathways. First, we revealed that mouse Abcg2 mediates urate transport using the membrane vesicle system. The export process by mouse Abcg2 was ATP-dependent and not saturable under the physiological concentration of urate. Then, we characterized the excretion of urate into urine, bile, and intestinal lumen using in vivo mouse model. SUA of Abcg2-knockout mice was significantly higher than that of control mice. Under this condition, the renal urate excretion was increased in Abcg2-knockout mice, whereas the urate excretion from the intestine was decreased to less than a half. Biliary urate excretion showed no significant difference regardless of Abcg2 genotype. From these results, we estimated the relative contribution of each pathway to total urate excretion; in wild-type mice, the renal excretion pathway contributes approximately two-thirds, the intestinal excretion pathway contributes one-third of the total urate excretion, and the urate excretion into bile is minor. Decreased intestinal excretion could account for the increased SUA of Abcg2-knockout mice. Thus, ABCG2 is suggested to have an important role in extra-renal urate excretion, especially in intestinal excretion. Accordingly, increased SUA in patients with ABCG2 dysfunction could be explained by the decreased excretion of urate from the intestine.

show abstract

“…When lacking uricase, UA cannot be converted into its soluble and excretable form, and as a consequence, its concentration is mainly controlled by endogenous metabolism (synthesis and cell turnover), and excretion and reabsorption in the kidney (Dehghan et al, 2008). Increasing evidence suggests that ABCG2, a high-capacity urate transporter, regulates serum UA levels by mediating urate excretion, and studies have shown that a decrease in ABCG2 protein expression levels is directly related to a decrease in urate transport activity (Matsuo, et al, 2009;Matsuo et al, 2013;Woodward et al, 2013). PDK2 is a gene that encodes for the kinase that phosphorylates serine 473 of Akt.…”

Section: Discussionmentioning

confidence: 99%

PDK2 and ABCG2 genes polymorphisms are correlated with blood glucose levels and uric acid in Tibetan gout patients

et al. 2016

View full text Add to dashboard Cite

ABSTRACT. Previous studies have shown that the PDK2 and ABCG2 genes play important roles in many aspects of gout development in European populations. However, a detailed genotype-phenotype analysis was not performed. The aim of the present study was to investigate the potential association between variants in these two genes and metabolismrelated quantitative phenotypes relevant to gout in a Chinese Tibetan population. In total, 316 Chinese Tibetan gout patients were recruited from rheumatology outpatient clinics and 6 single nucleotide polymorphisms in PDK2 and ABCG2 were genotyped, which were possible etiologic variants as identified in the HapMap Chinese Han Beijing population. A significant difference in blood glucose levels was detected between different genotypes of rs2728109 (P = 0.005) in the PDK2 gene. We also detected a significant difference in the mean serum uric levels between different genotypes of rs3114018 (P = 0.004) in the ABCG2 gene. All P values remained significant after Bonferroni's correction for multiple testing. Our data demonstrate potential roles for PDK2 and ABCG2 polymorphisms in the metabolic phenotypes of Tibetan gout patients, which may provide new insights into the etiology of gout. Further studies are required to confirm these findings.

show abstract

Common dysfunctional variants in ABCG2 are a major cause of early-onset gout

Cited by 110 publications

References 44 publications

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

ABCG2 Dysfunction Increases Serum Uric Acid by Decreased Intestinal Urate Excretion

PDK2 and ABCG2 genes polymorphisms are correlated with blood glucose levels and uric acid in Tibetan gout patients

Contact Info

Product

Resources

About