{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:47:06Z","timestamp":1791460026656,"version":"4.3.4"},"reference-count":63,"publisher":"SAGE Publications","issue":"9","license":[{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and\/or cellular defense to stress. The transcription factor Nrf2, encoded by\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      , is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      on the risk of developing HT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      In a case\u2013control candidate gene association study, functional SNPs in the\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      promoter (rs35652124, rs6706649, and rs6721961) were examined either as independent risk factors or in combination with a previously characterized HT risk allele (rs28665122) in the gene\n                      <jats:italic toggle=\"yes\">SELENOS<\/jats:italic>\n                      , encoding selenoprotein S (SelS). A total of 997 individuals from the north of Portugal (Porto) were enrolled, comprising 481 HT patients and 516 unrelated healthy controls.\n                      <jats:italic toggle=\"yes\">SELENOS<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      SNPs were genotyped using TaqMan\n                      <jats:sup>\u00ae<\/jats:sup>\n                      assays and Sanger sequencing, respectively. Odds ratios (ORs) were calculated using logistic regression, with adjustment for sex and age. Expression of SelS was analyzed by immunohistochemistry in thyroid tissue from HT patients and control subjects. Molecular interactions between the Nrf2 and SelS pathways were investigated in thyroid tissues from mice and in rat PCCL3 thyroid follicular cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      When all three\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      SNPs were considered together, the presence of one or more minor alleles was associated with a near-significant increased risk (OR\u2009=\u20091.43,\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.072). Among subjects harboring only major\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      alleles, there was no increased HT risk associated with heterozygosity or homozygosity for the\n                      <jats:italic toggle=\"yes\">SELENOS<\/jats:italic>\n                      minor allele. Conversely, in subjects heterozygous or homozygous for the\n                      <jats:italic toggle=\"yes\">SELENOS<\/jats:italic>\n                      risk allele, the presence of an\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      minor allele significantly increased HT risk by 2.8-fold (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009=\u20090.003). Immunohistochemistry showed reduced expression of SelS in thyroid follicular cells of HT patients. In Nrf2 knockout mice, there was reduced expression of SelS in thyroid follicular cells; conversely, in PCCL3 cells, reducing SelS expression caused reduced activity of Nrf2 signaling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">NFE2L2<\/jats:italic>\n                      promoter genotype interacts with the\n                      <jats:italic toggle=\"yes\">SELENOS<\/jats:italic>\n                      promoter genotype to modulate the risk of HT in a Portuguese population. This interaction may be due to a bidirectional positive feedback between the Nrf2 and SelS pathways.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2018.0480","type":"journal-article","created":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T03:49:45Z","timestamp":1566272985000},"page":"1302-1315","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":24,"title":["Interaction of Genetic Variations in\n                    <i>NFE2L2<\/i>\n                    and\n                    <i>SELENOS<\/i>\n                    Modulates the Risk of Hashimoto's Thyroiditis"],"prefix":"10.1177","volume":"29","author":[{"given":"Liliana R.","family":"Santos","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Hospital de Santa Maria, Lisbon, Portugal."},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal."},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cec\u00edlia","family":"Dur\u00e3es","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal."},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panos G.","family":"Ziros","sequence":"additional","affiliation":[{"name":"Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Pestana","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal."},{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), University of Porto, Porto, Portugal."},{"name":"Faculty of Medicine, University of Porto, Porto, Portugal."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"Esteves","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Porto, Porto, Portugal."},{"name":"Department of Endocrinology, Hospital of S. 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