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This genome-wide association study (GWAS) was designed to identify single nucleotide polymorphisms (SNPs) associated with common acute radiation-induced toxicities (RITs) in an HNC cohort.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>A two-stage GWAS was performed in 1279 HNC patients treated with RT and prospectively scored for mucositis, xerostomia, sticky saliva, and dysphagia. The area under the curve (AUC) was used to estimate the average load of toxicity during RT. At the discovery study, multivariate linear regression was used in 957 patients, and the top-ranking SNPs were tested in 322 independent replication cohort. Next, the discovery and the replication studies were meta-analyzed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A region on 5q21.3 containing 16 SNPs showed genome-wide (GW) significance association at P-value\u2009&lt;\u20095.0\u2009\u00d7\u200910<jats:sup>\u20138<\/jats:sup> with patient-rated acute xerostomia in the discovery study. The top signal was rs35542 with an adjusted effect size of 0.17*A (95% CI 0.12 to 0.23; P-value\u2009&lt;\u2009\u2009=\u20093.78\u2009\u00d7\u200910<jats:sup>\u20139<\/jats:sup>). The genome wide significant SNPs were located within three genes (<jats:italic>EFNA5, FBXL17,<\/jats:italic> and <jats:italic>FER<\/jats:italic>). <jats:italic>In-silico<\/jats:italic> functional analysis showed these genes may be involved in DNA damage response and co-expressed in minor salivary glands. We found 428 suggestive SNPs (P-value\u2009&lt;\u20091.0\u2009\u00d7\u200910<jats:sup>\u20135<\/jats:sup>) for other toxicities, taken to the replication study. Eleven of them showed a nominal association (P-value\u2009&lt;\u20090.05).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This GWAS suggested novel SNPs for patient-rated acute xerostomia in HNC patients. If validated, these SNPs and their related functional pathways could lead to a predictive assay to identify sensitive patients to radiation, which may eventually allow a more individualized RT treatment.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-021-03145-1","type":"journal-article","created":{"date-parts":[[2021,11,27]],"date-time":"2021-11-27T10:02:28Z","timestamp":1638007348000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A two-stage genome-wide association study of radiation-induced acute toxicity in head and neck cancer"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1671-7471","authenticated-orcid":false,"given":"Elnaz","family":"Naderi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Petra Gerarda","family":"Crijns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roel Johannes Henricus Marinus","family":"Steenbakkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna Geertruida Maria","family":"van den Hoek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrika Marike","family":"Boezen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behrooz Ziad","family":"Alizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes Albertus","family":"Langendijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,27]]},"reference":[{"issue":"6","key":"3145_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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The prospective data registration program has been reviewed by the medical ethical committee and is considered standard of care. Additional written informed consent was obtained for the genetic study (NCT02489084).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"481"}}