{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:16:42Z","timestamp":1784672202545,"version":"3.55.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,5,16]],"date-time":"2016-05-16T00:00:00Z","timestamp":1463356800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,5,16]],"date-time":"2016-05-16T00:00:00Z","timestamp":1463356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Gout is a common disease resulting from hyperuricemia. Recently, a genome-wide association study identified an association between gout and a single nucleotide polymorphism (SNP) rs2188380, located on an intergenic region between <jats:italic>MYL2<\/jats:italic> and <jats:italic>CUX2<\/jats:italic> on chromosome 12. However, other genes around rs2188380 could possibly be gout susceptibility genes. Therefore, we performed a fine-mapping study of the <jats:italic>MYL2-CUX2<\/jats:italic> region. From 8,595 SNPs in the <jats:italic>MYL2-CUX2<\/jats:italic> region, 9 tag SNPs were selected and genotyping of 1,048 male gout patients and 1,334 male controls was performed by TaqMan method. Eight SNPs showed significant associations with gout after Bonferroni correction. rs671 (Glu504Lys) of <jats:italic>ALDH2<\/jats:italic> had the most significant association with gout (<jats:italic>P<\/jats:italic>\u2009=\u20091.7\u2009\u00d7\u200910<jats:sup>\u221218<\/jats:sup>, odds ratio\u2009=\u20090.53). After adjustment for rs671, the other 8 SNPs no longer showed a significant association with gout, while the significant association of rs671 remained. rs671 has been reportedly associated with alcohol drinking behavior and it is well-known that alcohol drinking elevates serum uric acid levels. These data suggest that rs671, a common functional SNP of <jats:italic>ALDH2<\/jats:italic>, is a genuine gout-associated SNP in the <jats:italic>MYL2-CUX2<\/jats:italic> locus and that \u201cA\u201d allele (Lys) of rs671 plays a protective role in the development of gout.<\/jats:p>","DOI":"10.1038\/srep25360","type":"journal-article","created":{"date-parts":[[2016,5,16]],"date-time":"2016-05-16T09:55:15Z","timestamp":1463392515000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus"],"prefix":"10.1038","volume":"6","author":[{"given":"Masayuki","family":"Sakiyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirotaka","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Nakaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiyoshi","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayo","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rieko","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ooyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Shimizu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nariyoshi","family":"Shinomiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,16]]},"reference":[{"key":"BFsrep25360_CR1","doi-asserted-by":"publisher","first-page":"10338","DOI":"10.1073\/pnas.0901249106","volume":"106","author":"OM Woodward","year":"2009","unstructured":"Woodward, O. M. et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc. Natl. Acad. Sci. USA 106, 10338\u201310342 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep25360_CR2","doi-asserted-by":"publisher","first-page":"5ra11","DOI":"10.1126\/scitranslmed.3000237","volume":"1","author":"H Matsuo","year":"2009","unstructured":"Matsuo, H. et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci. Transl. Med. 1, 5ra11 (2009).","journal-title":"Sci. Transl. Med."},{"key":"BFsrep25360_CR3","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1038\/srep02014","volume":"3","author":"H Matsuo","year":"2013","unstructured":"Matsuo, H. et al. Common dysfunctional variants in ABCG2 are a major cause of early-onset gout. Sci. Rep. 3, 2014 (2013).","journal-title":"Sci. Rep"},{"key":"BFsrep25360_CR4","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1038\/ncomms1756","volume":"3","author":"K Ichida","year":"2012","unstructured":"Ichida, K. et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat. Commun. 3, 764 (2012).","journal-title":"Nat. Commun."},{"key":"BFsrep25360_CR5","doi-asserted-by":"publisher","first-page":"3755","DOI":"10.1038\/srep03755","volume":"4","author":"H Matsuo","year":"2014","unstructured":"Matsuo, H. et al. ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload. Sci. Rep. 4, 3755 (2014).","journal-title":"Sci. Rep"},{"key":"BFsrep25360_CR6","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1038\/ng.972","volume":"43","author":"P Sulem","year":"2011","unstructured":"Sulem, P. et al. Identification of low-frequency variants associated with gout and serum uric acid levels. Nat. Genet. 43, 1127\u20131130 (2011).","journal-title":"Nat. Genet."},{"key":"BFsrep25360_CR7","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/ng.2500","volume":"45","author":"A K\u00f6ttgen","year":"2013","unstructured":"K\u00f6ttgen, A. et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat. Genet. 45, 145\u2013154 (2013).","journal-title":"Nat. Genet."},{"key":"BFsrep25360_CR8","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1136\/annrheumdis-2014-206191","volume":"75","author":"H Matsuo","year":"2016","unstructured":"Matsuo, H. et al. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann. Rheum. Dis. 75, 652\u2013659 (2016).","journal-title":"Ann. Rheum. Dis."},{"key":"BFsrep25360_CR9","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1038\/ng.939","volume":"43","author":"YJ Kim","year":"2011","unstructured":"Kim, Y. J. et al. Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. Nat. Genet. 43, 990\u2013995 (2011).","journal-title":"Nat. Genet."},{"key":"BFsrep25360_CR10","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1242\/dev.013276","volume":"135","author":"A Iulianella","year":"2008","unstructured":"Iulianella, A., Sharma, M., Durnin, M., Vanden Heuvel, G. B. & Trainor, P. A. Cux2 (Cutl2) integrates neural progenitor development with cell-cycle progression during spinal cord neurogenesis. Development 135, 729\u2013741 (2008).","journal-title":"Development"},{"key":"BFsrep25360_CR11","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1126\/science.1223616","volume":"337","author":"SJ Franco","year":"2012","unstructured":"Franco, S. J. et al. Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 337, 746\u2013749 (2012).","journal-title":"Science"},{"key":"BFsrep25360_CR12","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1038\/ejhg.2012.3","volume":"20","author":"J Huang","year":"2012","unstructured":"Huang, J., Ellinghaus, D., Franke, A., Howie, B. & Li, Y. 1000 Genomes-based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data. Eur. J. Hum. Genet. 20, 801\u2013805 (2012).","journal-title":"Eur. J. Hum. Genet."},{"key":"BFsrep25360_CR13","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1158\/1055-9965.EPI-05-0911","volume":"15","author":"K Matsuo","year":"2006","unstructured":"Matsuo, K. et al. Alcohol dehydrogenase 2 His47Arg polymorphism influences drinking habit independently of aldehyde dehydrogenase 2 Glu487Lys polymorphism: analysis of 2,299 Japanese subjects. Cancer Epidemiol. Biomarkers Prev. 15, 1009\u20131013 (2006).","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"BFsrep25360_CR14","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/978-1-4615-2584-4_13","volume":"370","author":"H Yamanaka","year":"1994","unstructured":"Yamanaka, H. et al. Analysis of the genotypes for aldehyde dehydrogenase 2 in Japanese patients with primary gout. Adv. Exp. Med. Biol. 370, 53\u201356 (1994).","journal-title":"Adv. Exp. Med. Biol."},{"key":"BFsrep25360_CR15","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1253\/circj.CJ-10-0774","volume":"75","author":"F Takeuchi","year":"2011","unstructured":"Takeuchi, F. et al. Confirmation of ALDH2 as a major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circ. J. 75, 911\u2013918 (2011).","journal-title":"Circ. J."},{"key":"BFsrep25360_CR16","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1007\/BF00197271","volume":"88","author":"HW Goedde","year":"1992","unstructured":"Goedde, H. W. et al. Distribution of ADH2 and ALDH2 genotypes in different populations. Hum. Genet. 88, 344\u2013346 (1992).","journal-title":"Hum. Genet."},{"key":"BFsrep25360_CR17","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1002\/art.1780200320","volume":"20","author":"SL Wallace","year":"1977","unstructured":"Wallace, S. L. et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 20, 895\u2013900 (1977).","journal-title":"Arthritis Rheum."},{"key":"BFsrep25360_CR18","first-page":"317","volume":"8","author":"N Hamajima","year":"2007","unstructured":"Hamajima, N. & J-MICC Study Group. The Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study) to detect gene-environment interactions for cancer. Asian Pac. J. Cancer Prev. 8, 317\u2013323 (2007).","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"BFsrep25360_CR19","first-page":"137","volume":"71","author":"Y Asai","year":"2009","unstructured":"Asai, Y. et al. Baseline data of Shizuoka area in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Nagoya J. Med. Sci. 71, 137\u2013144 (2009).","journal-title":"Nagoya J. Med. Sci."},{"key":"BFsrep25360_CR20","doi-asserted-by":"crossref","unstructured":"International HapMap, C. The International HapMap Project. Nature 426, 789\u2013796 (2003).","DOI":"10.1038\/nature02168"},{"key":"BFsrep25360_CR21","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/j.ajhg.2008.11.001","volume":"83","author":"H Matsuo","year":"2008","unstructured":"Matsuo, H. et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am. J. Hum. Genet. 83, 744\u2013751 (2008).","journal-title":"Am. J. Hum. Genet."},{"key":"BFsrep25360_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13577-013-0081-8","volume":"27","author":"M Sakiyama","year":"2014","unstructured":"Sakiyama, M. et al. Common variant of leucine-rich repeat-containing 16A (LRRC16A) gene is associated with gout susceptibility. Hum. Cell 27, 1\u20134 (2014).","journal-title":"Hum. Cell"},{"key":"BFsrep25360_CR23","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/ncomms1033","volume":"1","author":"J Li","year":"2010","unstructured":"Li, J. et al. Identification of high-quality cancer prognostic markers and metastasis network modules. Nat. Commun. 1, 34 (2010).","journal-title":"Nat. Commun."},{"key":"BFsrep25360_CR24","doi-asserted-by":"crossref","unstructured":"Efron, B. & Tibshirani, R. J. In An Introduction to the Bootstrap (eds Cox, D. R. et al.) 202\u2013219 (Chapman & Hall, 1993).","DOI":"10.1007\/978-1-4899-4541-9_15"},{"key":"BFsrep25360_CR25","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559\u2013575 (2007).","journal-title":"Am. J. Hum. Genet."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep25360","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep25360.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep25360.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T14:50:07Z","timestamp":1672843807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep25360"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,16]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,6]]}},"alternative-id":["BFsrep25360"],"URL":"https:\/\/doi.org\/10.1038\/srep25360","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,16]]},"assertion":[{"value":"18 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 April 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 May 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Yes, there is potential competing interest: H.M. and N.S. have a patent pending based on the work reported in this paper.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"25360"}}