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Golden Retrievers appear predisposed, representing over 40% of TZL cases. Prior research found that asymptomatic aged Golden Retrievers frequently have populations of T zone-like cells (phenotypically identical to TZL) of undetermined significance (TZUS), potentially representing a pre-clinical state. These findings suggest a genetic risk factor for this disease and caused us to investigate potential genes of interest using a genome-wide association study of privately-owned U.S. Golden Retrievers.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Dogs were categorized as TZL (<jats:italic>n<\/jats:italic>\u2009=\u200995), TZUS (<jats:italic>n<\/jats:italic>\u2009=\u2009142), or control (<jats:italic>n<\/jats:italic>\u2009=\u2009101) using flow cytometry and genotyped using the Illumina CanineHD BeadChip. Using a mixed linear model adjusting for population stratification, we found association with genome-wide significance in regions on chromosomes 8 and 14. The chromosome 14 peak included four SNPs (Odds Ratio\u2009=\u20091.18\u20131.19, <jats:italic>p<\/jats:italic>\u2009=\u2009.3\u2009\u00d7\u200910<jats:sup>\u2212\u20095<\/jats:sup>\u20135.1\u2009\u00d7\u200910<jats:sup>\u2212\u20095<\/jats:sup>) near three hyaluronidase genes (<jats:italic>SPAM1, HYAL4,<\/jats:italic> and <jats:italic>HYALP1<\/jats:italic>). Targeted resequencing of this region using a custom sequence capture array identified missense mutations in all three genes; the variant in <jats:italic>SPAM1<\/jats:italic> was predicted to be damaging. These mutations were also associated with risk for mast cell tumors among Golden Retrievers in an unrelated study. The chromosome 8 peak contained 7 SNPs (Odds Ratio\u2009=\u20091.24\u20131.42, <jats:italic>p<\/jats:italic>\u2009=\u20092.7\u2009\u00d7\u200910<jats:sup>\u2212\u20097<\/jats:sup>\u20137.5\u2009\u00d7\u200910<jats:sup>\u2212\u20095<\/jats:sup>) near genes involved in thyroid hormone regulation (<jats:italic>DIO2<\/jats:italic> and <jats:italic>TSHR<\/jats:italic>). A prior study from our laboratory found hypothyroidism is inversely associated with TZL risk. No coding mutations were found with targeted resequencing but identified variants may play a regulatory role for all or some of the genes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>The pathogenesis of canine TZL may be related to hyaluronan breakdown and subsequent production of pro-inflammatory and pro-oncogenic byproducts. The association on chromosome 8 may indicate thyroid hormone is involved in TZL development, consistent with findings from a previous study evaluating epidemiologic risk factors for TZL. Future work is needed to elucidate these mechanisms.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12864-020-06872-9","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T12:03:44Z","timestamp":1594037024000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Genome-wide association analysis of canine T zone lymphoma identifies link to hypothyroidism and a shared association with mast-cell tumors"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9942-7797","authenticated-orcid":false,"given":"Julia D.","family":"Labadie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingegerd","family":"Elvers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather Spencer","family":"Feigelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheryl","family":"Magzamen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Yoshimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Dossey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Burnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne C.","family":"Avery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,6]]},"reference":[{"issue":"3\u20134","key":"6872_CR1","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.vetimm.2014.02.016","volume":"159","author":"D Ito","year":"2014","unstructured":"Ito D, Frantz AM, Modiano JF. 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Our research did not meet the requirements of the federal definition of human subject research and thus was considered exempt from IRB by the Colorado State University Research Integrity and Compliance Review Office. Written informed consent was obtained from all dog owners prior to enrolling in the study. Venous blood samples were obtained according to the protocol of the submitting veterinary clinic and dogs were immediately returned to the owner\u2019s custody. This IACUC protocol fell under USDA pain category C as venous blood draws involve no more than momentary pain or distress.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"464"}}