{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:45:40Z","timestamp":1790127940173,"version":"4.0.1"},"reference-count":161,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T00:00:00Z","timestamp":1618704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["109 - 2314 - B - 037 - 123"],"award-info":[{"award-number":["109 - 2314 - B - 037 - 123"]}]},{"name":"Kaohsiung Medical University Hospital","award":["KMUH109 - 9R22"],"award-info":[{"award-number":["KMUH109 - 9R22"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients.<\/jats:p>","DOI":"10.3390\/ijms22084187","type":"journal-article","created":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T22:15:13Z","timestamp":1618784113000},"page":"4187","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases"],"prefix":"10.3390","volume":"22","author":[{"given":"Chia-Chun","family":"Tseng","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-Chun","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4281-1082","authenticated-orcid":false,"given":"Wei-Ting","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-2335","authenticated-orcid":false,"given":"Chung-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Chen","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory Diagnosis of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1291-1739","authenticated-orcid":false,"given":"Jeng-Hsien","family":"Yen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan"},{"name":"Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan"},{"name":"Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan"},{"name":"Department of Biological Science and Technology, National Chiao-Tung University, Hsinchu 30010, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-Jen","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung 81148, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9362","DOI":"10.1073\/pnas.0903103106","article-title":"Potential etiologic and functional implications of genome-wide association loci for human diseases and traits","volume":"106","author":"Hindorff","year":"2009","journal-title":"Proc. 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