{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:36:33Z","timestamp":1789950993874,"version":"4.0.1"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2314-B-303 -026 -MY3"],"award-info":[{"award-number":["MOST 108-2314-B-303 -026 -MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2314-B-303-012, MOST 109-2314-B-303-021-MY2"],"award-info":[{"award-number":["MOST 108-2314-B-303-012, MOST 109-2314-B-303-021-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005925","name":"Buddhist Tzu Chi Medical Foundation","doi-asserted-by":"publisher","award":["TCRD-TPE-108-61, TCRD-TPE-109-RT-1"],"award-info":[{"award-number":["TCRD-TPE-108-61, TCRD-TPE-109-RT-1"]}],"id":[{"id":"10.13039\/501100005925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MUC1 is a transmembrane mucin involved in carcinogenesis and cell signaling. Functional MUC1 variants are associated with multiple metabolic and biochemical traits. This study investigated the association of functional MUC1 variants with MUC1 DNA methylation and various metabolic, biochemical, and hematological parameters. In total, 80,728 participants from the Taiwan Biobank were enrolled for association analysis using functional MUC1 variants and a nearby gene regional plot association study. A subgroup of 1686 participants was recruited for MUC1 DNA methylation analysis. After Bonferroni correction, we found that two MUC1 variants, rs4072037 and rs12411216, were significantly associated with waist circumference, systolic blood pressure, hemoglobin A1C, renal functional parameters (blood urea nitrogen, serum creatinine levels, and estimated glomerular filtration rate), albuminuria, hematocrit, hemoglobin, red blood cell count, serum uric acid level, and gout risk, with both favorable and unfavorable effects. Causal inference analysis revealed that the association between the variants and gout was partially dependent on the serum uric acid level. Both gene variants showed genome-wide significant associations with MUC1 gene-body methylation. Regional plot association analysis further revealed lead single-nucleotide polymorphisms situated at the nearby TRIM46\u2013MUC1\u2013THBS3\u2013MTX1 gene region for the studied phenotypes. In conclusion, our data demonstrated the pleiotropic effects of MUC1 variants with novel associations for gout, red blood cell parameters, and MUC1 DNA methylation. These results provide further evidence in understanding the critical role of TRIM46\u2013MUC1\u2013THBS3\u2013MTX1 gene region variants in the pathogenesis of cardiometabolic, renal, and hematological disorders.<\/jats:p>","DOI":"10.3390\/ijms221910641","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T10:55:40Z","timestamp":1633085740000},"page":"10641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Pleiotropic Effects of Functional MUC1 Variants on Cardiometabolic, Renal, and Hematological Traits in the Taiwanese Population"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4140-5699","authenticated-orcid":false,"given":"Ming-Sheng","family":"Teng","sequence":"first","affiliation":[{"name":"Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Semon","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Life Science, Chinese Culture University, Taipei 11114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0012-2804","authenticated-orcid":false,"given":"Lung-An","family":"Hsu","sequence":"additional","affiliation":[{"name":"The First Cardiovascular Division, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 33305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Hua","family":"Chou","sequence":"additional","affiliation":[{"name":"The Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"},{"name":"School of Medicine, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8218-6827","authenticated-orcid":false,"given":"Yu-Lin","family":"Ko","sequence":"additional","affiliation":[{"name":"Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"},{"name":"The Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"},{"name":"School of Medicine, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4475","DOI":"10.1007\/s00018-015-2014-z","article-title":"MUC1 (CD227): A multi-tasked molecule","volume":"72","author":"Apostolopoulos","year":"2015","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s10719-015-9606-6","article-title":"Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases","volume":"32","author":"Behera","year":"2015","journal-title":"Glycoconj. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.molmed.2014.02.007","article-title":"MUC1: A multifaceted oncoprotein with a key role in cancer progression","volume":"20","author":"Nath","year":"2014","journal-title":"Trends Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"554","DOI":"10.2174\/0929867324666170817151954","article-title":"MUC1 Story: Great Expectations, Disappointments and the Renaissance","volume":"26","author":"Syrkina","year":"2019","journal-title":"Curr. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1006\/cimm.2000.1643","article-title":"The epithelial mucin, MUC1, is expressed on resting T lymphocytes and can function as a negative regulator of T cell activation","volume":"201","author":"Chang","year":"2000","journal-title":"Cell. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1023\/A:1011379725811","article-title":"MUC1, the renaissance molecule","volume":"6","author":"Gendler","year":"2001","journal-title":"J. Mammary Gland. Biol. Neoplasia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1046\/j.1365-2141.2003.04038.x","article-title":"Regulated expression of MUC1 epithelial antigen in erythropoiesis","volume":"120","author":"Rughetti","year":"2003","journal-title":"Br. J. Haematol."},{"key":"ref_8","first-page":"1541","article-title":"The MUC gene family: Their role in the diagnosis and prognosis of gastric cancer","volume":"23","author":"Senapati","year":"2008","journal-title":"Histol. Histopathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0925-4439(99)00055-1","article-title":"MUC1 and cancer","volume":"1455","author":"Burchell","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ahn, H.S., Kim, J.H., Jeong, H., Yu, J., Yeom, J., Song, S.H., Kim, S.S., Kim, I.J., and Kim, K. (2020). Differential Urinary Proteome Analysis for Predicting Prognosis in Type 2 Diabetes Patients with and without Renal Dysfunction. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124236"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/ki.2014.125","article-title":"Autosomal dominant tubulointerstitial kidney disease: Of names and genes","volume":"86","author":"Bleyer","year":"2014","journal-title":"Kidney Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41572-019-0109-9","article-title":"Autosomal dominant tubulointerstitial kidney disease","volume":"5","author":"Devuyst","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/ki.2015.28","article-title":"Autosomal dominant tubulointerstitial kidney disease: Diagnosis, classification, and management\u2014A KDIGO consensus report","volume":"88","author":"Eckardt","year":"2015","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/ng.3342","article-title":"Loss-of-function variants in ATM confer risk of gastric cancer","volume":"47","author":"Helgason","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1053\/j.gastro.2010.10.058","article-title":"A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer","volume":"140","author":"Saeki","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1136\/gutjnl-2015-310612","article-title":"Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: Pooled results from two Chinese genome-wide association studies","volume":"66","author":"Wang","year":"2017","journal-title":"Gut"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41588-018-0047-6","article-title":"Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases","volume":"50","author":"Kanai","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Meyer, T.E., Verwoert, G.C., Hwang, S.J., Glazer, N.L., Smith, A.V., van Rooij, F.J., Ehret, G.B., Boerwinkle, E., Felix, J.F., and Leak, T.S. (2010). Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001045"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5052","DOI":"10.1038\/s41467-018-07345-0","article-title":"Interethnic analyses of blood pressure loci in populations of East Asian and European descent","volume":"9","author":"Takeuchi","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4800","DOI":"10.1038\/s41467-018-07260-4","article-title":"Molecular insights into genome-wide association studies of chronic kidney disease-defining traits","volume":"9","author":"Xu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"803","DOI":"10.2337\/db15-1313","article-title":"Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes","volume":"65","author":"Teumer","year":"2016","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"235","DOI":"10.2217\/14622416.9.2.235","article-title":"Taiwan Biobank: A project aiming to aid Taiwan\u2019s transition into a biomedical island","volume":"9","author":"Fan","year":"2008","journal-title":"Pharmacogenomics"},{"key":"ref_23","first-page":"5321","article-title":"Population structure of Han Chinese in the modern Taiwanese population based on 10,000 participants in the Taiwan Biobank project","volume":"25","author":"Chen","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1016\/S0140-6736(10)60674-5","article-title":"Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis","volume":"375","author":"Matsushita","year":"2010","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4130","DOI":"10.1038\/s41467-019-11576-0","article-title":"Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria","volume":"10","author":"Teumer","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/s42003-019-0339-0","article-title":"Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals","volume":"2","author":"Nakatochi","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1136\/annrheumdis-2020-219796","article-title":"Variants in urate transporters, ADH1B, GCKR and MEPE genes associate with transition from asymptomatic hyperuricaemia to gout: Results of the first gout versus asymptomatic hyperuricaemia GWAS in Caucasians using data from the UK Biobank","volume":"80","author":"Morgan","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.jaci.2019.09.035","article-title":"Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank","volume":"145","author":"Zhu","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1200\/JCO.1999.17.5.1535","article-title":"Expression of MUC-1 epitopes on normal bone marrow: Implications for the detection of micrometastatic tumor cells","volume":"17","author":"Brugger","year":"1999","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.cell.2016.10.042","article-title":"The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease","volume":"167","author":"Astle","year":"2016","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/sj.bjc.6604617","article-title":"Genetic regulation of MUC1 alternative splicing in human tissues","volume":"99","author":"Ng","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/mc.21966","article-title":"G-A variant in miR-200c binding site of EFNA1 alters susceptibility to gastric cancer","volume":"53","author":"Li","year":"2014","journal-title":"Mol. Carcinog."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s13041-020-00637-x","article-title":"Characterization of a pathogenic variant in GBA for Parkinson\u2019s disease with mild cognitive impairment patients","volume":"13","author":"Jiang","year":"2020","journal-title":"Mol. Brain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/mds.26359","article-title":"GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson\u2019s disease","volume":"31","author":"Mata","year":"2016","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1073\/pnas.1220464110","article-title":"Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies","volume":"110","author":"Sardi","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0092-8674(85)90312-5","article-title":"A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA","volume":"40","author":"Bird","year":"1985","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/nature08514","article-title":"Human DNA methylomes at base resolution show widespread epigenomic differences","volume":"462","author":"Lister","year":"2009","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1101\/gr.147942.112","article-title":"Dynamic DNA methylation across diverse human cell lines and tissues","volume":"23","author":"Varley","year":"2013","journal-title":"Genome Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41580-019-0159-6","article-title":"The diverse roles of DNA methylation in mammalian development and disease","volume":"20","author":"Greenberg","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nature10442","article-title":"CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing","volume":"479","author":"Shukla","year":"2011","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/cr.2013.110","article-title":"Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition","volume":"23","author":"Maunakea","year":"2013","journal-title":"Cell Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.atherosclerosis.2021.01.014","article-title":"Circulating chemerin levels are determined through circulating platelet counts in nondiabetic Taiwanese people: A bidirectional Mendelian randomization study","volume":"320","author":"Hsu","year":"2021","journal-title":"Atherosclerosis"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:08:13Z","timestamp":1760166493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,30]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910641"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910641","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,30]]}}}