{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T23:22:12Z","timestamp":1785453732839,"version":"3.56.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,8,10]],"date-time":"2016-08-10T00:00:00Z","timestamp":1470787200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,8,10]],"date-time":"2016-08-10T00:00:00Z","timestamp":1470787200000},"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>Chromosome 4q25 has been identified as a genomic region associated with gout. However, the associations of gout with the genes in this region have not yet been confirmed. Here, we performed two-stage analysis to determine whether variations in candidate genes in the 4q25 region are associated with gout in a male Chinese Han population. We first evaluated 96 tag single nucleotide polymorphisms (SNPs) in eight inflammatory\/immune pathway- or glucose\/lipid metabolism-related genes in the 4q25 region in 480 male gout patients and 480 controls. The SNP rs12504538, located in the elongation of very-long-chain-fatty-acid-like family member 6 gene (<jats:italic>Elovl6<\/jats:italic>), was found to be associated with gout susceptibility (<jats:italic>P<\/jats:italic><jats:sub>adjusted<\/jats:sub>\u2009=\u20090.00595). In the second stage of analysis, we performed fine mapping analysis of 93 tag SNPs in <jats:italic>Elovl6<\/jats:italic> and in the epidermal growth factor gene (<jats:italic>EGF<\/jats:italic>) and its flanking regions in 1017 male patients gout and 1897 healthy male controls. We observed a significant association between the T allele of <jats:italic>EGF<\/jats:italic> rs2298999 and gout (odds ratio\u2009=\u20090.77, 95% confidence interval\u2009=\u20090.67\u20130.88, <jats:italic>P<\/jats:italic><jats:sub>adjusted<\/jats:sub>\u2009=\u20096.42\u2009\u00d7\u200910<jats:sup>\u22123<\/jats:sup>). These results provide the first evidence for an association between the <jats:italic>EGF<\/jats:italic> rs2298999 C\/T polymorphism and gout. Our findings should be validated in additional populations.<\/jats:p>","DOI":"10.1038\/srep31082","type":"journal-article","created":{"date-parts":[[2016,8,10]],"date-time":"2016-08-10T09:32:47Z","timestamp":1470821567000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Epidermal growth factor gene is a newly identified candidate gene for gout"],"prefix":"10.1038","volume":"6","author":[{"given":"Lin","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunwei","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaotong","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiguo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruosai","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinde","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changgui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,8,10]]},"reference":[{"key":"BFsrep31082_CR1","first-page":"540","volume":"25","author":"AL Ar\u2019ev","year":"2012","unstructured":"Ar\u2019ev, A. L., Kunitskaia, N. A. & Kozina, L. S. Gout and hyperuricemia today: prevalence, risk factors, features in the elderly. Adv Gerontol 25, 540\u2013544 (2012).","journal-title":"Adv Gerontol"},{"key":"BFsrep31082_CR2","first-page":"1859","volume":"35","author":"Z Miao","year":"2008","unstructured":"Miao, Z. et al. Dietary and lifestyle changes associated with high prevalence of hyperuricemia and gout in the Shandong coastal cities of Eastern China. J Rheumatol 35, 1859\u20131864 (2008).","journal-title":"China. J Rheumatol"},{"key":"BFsrep31082_CR3","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1007\/s11926-007-0041-y","volume":"9","author":"JS Sundy","year":"2007","unstructured":"Sundy, J. S. & Hershfield, M. S. Uricase and other novel agents for the management of patients with treatment-failure gout. Curr Rheumatol Rep 9, 258\u2013264 (2007).","journal-title":"Curr Rheumatol Rep"},{"key":"BFsrep31082_CR4","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s11926-012-0307-x","volume":"15","author":"JA Singh","year":"2013","unstructured":"Singh, J. A. Racial and gender disparities among patients with gout. Curr Rheumatol Rep 15, 307 (2013).","journal-title":"Curr Rheumatol Rep"},{"key":"BFsrep31082_CR5","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1038\/nrrheum.2012.144","volume":"8","author":"AM Reginato","year":"2012","unstructured":"Reginato, A. M., Mount, D. B., Yang, I. & Choi, H. K. The genetics of hyperuricaemia and gout. Nat Rev Rheumatol 8, 610\u2013621 (2012).","journal-title":"Nat Rev Rheumatol"},{"key":"BFsrep31082_CR6","doi-asserted-by":"publisher","first-page":"e24561","DOI":"10.1371\/journal.pone.0024561","volume":"7","author":"C Li","year":"2012","unstructured":"Li, C. et al. Polymorphisms in the presumptive promoter region of the SLC2A9 gene are associated with gout in a Chinese male population. PloS One 7, e24561 (2012).","journal-title":"PloS One"},{"key":"BFsrep31082_CR7","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1136\/jmg.2009.068619","volume":"47","author":"C Li","year":"2010","unstructured":"Li, C. et al. Multiple single nucleotide polymorphisms in the human urate transporter 1 (hURAT1) gene are associated with hyperuricaemia in Han Chinese. J Med Genet 47, 204\u2013210 (2010).","journal-title":"J Med Genet"},{"key":"BFsrep31082_CR8","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1007\/s00439-012-1151-9","volume":"131","author":"J Wang","year":"2012","unstructured":"Wang, J. et al. Association between gout and polymorphisms in GCKR in male Han Chinese. Hum Genet 131, 1261\u20131265 (2012).","journal-title":"Hum Genet"},{"key":"BFsrep31082_CR9","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1038\/ng.2500","volume":"45","author":"A Kottgen","year":"2013","unstructured":"Kottgen, 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":"BFsrep31082_CR10","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1136\/annrheumdis-2014-205877","volume":"75","author":"AJ Phipps-Green","year":"2016","unstructured":"Phipps-Green, A. J. et al. Twenty-eight loci that influence serum urate levels: analysis of association with gout. Ann Rheum Dis 75, 124\u2013130 (2016).","journal-title":"Ann Rheum Dis"},{"key":"BFsrep31082_CR11","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.3899\/jrheum.121244","volume":"40","author":"W Urano","year":"2013","unstructured":"Urano, W. et al. Effect of genetic polymorphisms on development of gout. J Rheumatol 40, 1374\u20131378 (2013).","journal-title":"J Rheumatol"},{"key":"BFsrep31082_CR12","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/s13075-015-0609-2","volume":"17","author":"TR Merriman","year":"2015","unstructured":"Merriman, T. R. An update on the genetic architecture of hyperuricemia and gout. Arthritis Res Ther 17, 98 (2015).","journal-title":"Arthritis Res Ther"},{"key":"BFsrep31082_CR13","doi-asserted-by":"publisher","first-page":"7041","DOI":"10.1038\/ncomms8041","volume":"6","author":"C Li","year":"2015","unstructured":"Li, C. et al. Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese. Nat Commun 6, 7041 (2015).","journal-title":"Nat Commun"},{"key":"BFsrep31082_CR14","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1086\/423429","volume":"75","author":"LS Cheng","year":"2004","unstructured":"Cheng, L. S. et al. Genomewide scan for gout in taiwanese aborigines reveals linkage to chromosome 4q25.Am J Hum Genet 75, 498\u2013503 (2004).","journal-title":"Am J Hum Genet"},{"key":"BFsrep31082_CR15","first-page":"243","volume":"23","author":"C Li","year":"2007","unstructured":"Li, C. et al. Chromosomal localization of primary gout susceptibility gene in a Chinese pedigree. Chin. J. Endocrinol. Metab (in Chinese) 23, 243\u2013245 (2007).","journal-title":"Chin. J. Endocrinol. Metab (in Chinese)"},{"key":"BFsrep31082_CR16","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.plipres.2010.12.001","volume":"50","author":"M Murakami","year":"2011","unstructured":"Murakami, M. et al. Recent progress in phospholipase A(2) research: from cells to animals to humans. Prog Lipid Res 50, 152\u2013192 (2011).","journal-title":"Prog Lipid Res"},{"key":"BFsrep31082_CR17","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.biochi.2010.03.015","volume":"92","author":"M Murakami","year":"2010","unstructured":"Murakami, M. et al. Emerging roles of secreted phospholipase A2 enzymes: Lessons from transgenic and knockout mice. Biochimie. 92, 561\u2013582 (2010).","journal-title":"Biochimie."},{"key":"BFsrep31082_CR18","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1146\/annurev.biochem.76.062405.154007","volume":"77","author":"G Lambeau","year":"2008","unstructured":"Lambeau, G. & Gelb, M. H. Biochemistry and physiology of mammalian secreted phospholipases A2. Annu Rev Biochem 77, 495\u2013520 (2008).","journal-title":"Annu Rev Biochem"},{"key":"BFsrep31082_CR19","doi-asserted-by":"publisher","first-page":"563","DOI":"10.3109\/1354750X.2014.946450","volume":"19","author":"L Wang","year":"2014","unstructured":"Wang, L. et al. EGF rs11568835 G\/A polymorphism is associated with increased risk of rheumatoid arthritis. Biomarkers 19, 563\u2013566 (2014).","journal-title":"Biomarkers"},{"key":"BFsrep31082_CR20","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1016\/j.lfs.2012.04.003","volume":"90","author":"YR Zhao","year":"2012","unstructured":"Zhao, Y. R., Dong, J. B., Li, Y. & Wu, M. P. Sphingomyelin synthase 2 over-expression induces expression of aortic inflammatory biomarkers and decreases circulating EPCs in ApoE KO mice. Life Sci 90, 867\u2013873 (2012).","journal-title":"Life Sci"},{"key":"BFsrep31082_CR21","doi-asserted-by":"publisher","first-page":"e21198","DOI":"10.1371\/journal.pone.0021198","volume":"6","author":"S Morcillo","year":"2011","unstructured":"Morcillo, S. et al. ELOVL6 genetic variation is related to insulin sensitivity: a new candidate gene in energy metabolism. PloS One 6, e21198 (2011).","journal-title":"PloS One"},{"key":"BFsrep31082_CR22","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.kjms.2014.01.003","volume":"30","author":"CM Chen","year":"2014","unstructured":"Chen, C. M. et al. Heat shock induces expression of OSTC\/DC2, a novel subunit of oligosaccharyltransferase, in vitro and in vivo. Kaohsiung J Med Sci 30, 219\u2013223 (2014).","journal-title":"Kaohsiung J Med Sci"},{"key":"BFsrep31082_CR23","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.plefa.2010.06.005","volume":"83","author":"A Devos","year":"2010","unstructured":"Devos, A. et al. Genetic polymorphism of CYP2U1, a cytochrome P450 involved in fatty acids hydroxylation. Prostaglandins Leukot Essent Fatty Acids 83, 105\u2013110 (2010).","journal-title":"Prostaglandins Leukot Essent Fatty Acids"},{"key":"BFsrep31082_CR24","doi-asserted-by":"publisher","first-page":"R119","DOI":"10.1530\/JME-15-0016","volume":"54","author":"SA Rahman","year":"2015","unstructured":"Rahman, S. A., Nessa, A. & Hussain, K. Molecular mechanisms of congenital hyperinsulinism. J Mol Endocrinol 54, R119\u2013129 (2015).","journal-title":"J Mol Endocrinol"},{"key":"BFsrep31082_CR25","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/ng.106","volume":"40","author":"V Vitart","year":"2008","unstructured":"Vitart, V. et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 40, 437\u2013442(2008).","journal-title":"Nat Genet"},{"key":"BFsrep31082_CR26","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/ng.107","volume":"40","author":"A Doring","year":"2008","unstructured":"Doring, A. et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 40, 430\u2013436(2008).","journal-title":"Nat Genet"},{"key":"BFsrep31082_CR27","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 (2015)."},{"key":"BFsrep31082_CR28","doi-asserted-by":"publisher","first-page":"150","DOI":"10.3109\/03009742.2012.726372","volume":"42","author":"S Liu","year":"2013","unstructured":"Liu, S. et al. IL-8 -251T\/A and IL-12B 1188A\/C polymorphisms are associated with gout in a Chinese male population. Scand J Rheumatol 42, 150\u2013158 (2013).","journal-title":"Scand J Rheumatol"},{"key":"BFsrep31082_CR29","unstructured":"GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science 8, 648\u2013660 (2015)."},{"key":"BFsrep31082_CR30","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1634\/theoncologist.12-2-201","volume":"12","author":"A Araujo","year":"2007","unstructured":"Araujo, A. et al. Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer\u2014a review of the literature. Oncologist 12, 201\u2013210 (2007).","journal-title":"Oncologist"},{"key":"BFsrep31082_CR31","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1093\/ije\/dyt028","volume":"42","author":"AM Ko","year":"2013","unstructured":"Ko, A. M. et al. ALPK1 genetic regulation and risk in relation to gout. Int J Epidemiol 42, 466\u2013474 (2013).","journal-title":"Int J Epidemiol"},{"key":"BFsrep31082_CR32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s13577-014-0103-1","volume":"28","author":"T Chiba","year":"2015","unstructured":"Chiba, T. et al. Common variant of ALPK1 is not associated with gout: a replication study. Hum Cell 28, 1\u20134 (2015).","journal-title":"Hum Cell"},{"key":"BFsrep31082_CR33","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.1093\/bioinformatics\/btn564","volume":"24","author":"AD ohnson","year":"2008","unstructured":"ohnson, A. D. et al. SNAP: A web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24, 2938\u20132939 (2008).","journal-title":"Bioinformatics"},{"key":"BFsrep31082_CR34","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1136\/ard.2008.093252","volume":"68","author":"SJ Chang","year":"2009","unstructured":"Chang, S. J. et al. The cyclic GMP-dependent protein kinase II gene associates with gout disease: identified by genome-wide analysis and case-control study. Ann Rheum Dis 68, 1213\u20131219 (2009).","journal-title":"Ann Rheum Dis"},{"key":"BFsrep31082_CR35","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.3899\/jrheum.131548","volume":"41","author":"M Sakiyama","year":"2014","unstructured":"Sakiyama, M. et al. Common variants of cGKII\/PRKG2 are not associated with gout susceptibility. J Rheumatol 41, 1395\u20131397 (2014).","journal-title":"J Rheumatol"},{"key":"BFsrep31082_CR36","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.1016\/S0140-6736(08)61343-4","volume":"372","author":"A Dehghan","year":"2008","unstructured":"Dehghan, A. et al. Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 372, 1953\u20131961(2008).","journal-title":"Lancet"},{"key":"BFsrep31082_CR37","doi-asserted-by":"publisher","first-page":"e1000504","DOI":"10.1371\/journal.pgen.1000504","volume":"5","author":"M Kolz","year":"2009","unstructured":"Kolz, M. et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet 5, e1000504 (2009)","journal-title":"PLoS Genet"},{"key":"BFsrep31082_CR38","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":"BFsrep31082_CR39","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"},{"key":"BFsrep31082_CR40","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1093\/bioinformatics\/bth457","volume":"21","author":"JC Barrett","year":"2005","unstructured":"Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263\u2013265 (2005).","journal-title":"Bioinformatics"},{"key":"BFsrep31082_CR41","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1093\/bioinformatics\/19.1.149","volume":"19","author":"S Purcell","year":"2003","unstructured":"Purcell, S., Cherny, S. S. & Sham, P. C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149\u2013150 (2003).","journal-title":"Bioinformatics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep31082","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31082.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep31082.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T21:18:06Z","timestamp":1672867086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep31082"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8,10]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,11,14]]}},"alternative-id":["BFsrep31082"],"URL":"https:\/\/doi.org\/10.1038\/srep31082","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8,10]]},"assertion":[{"value":"19 October 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 August 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"31082"}}