Editing Hashimoto's thyroiditis (section)

=== Genetics ===
Thyroid autoimmunity can be [[Heredity|familial]].<ref name="Dayan96">{{cite journal | vauthors = Dayan CM, Daniels GH | title = Chronic autoimmune thyroiditis | journal = The New England Journal of Medicine | volume = 335 | issue = 2 | pages = 99–107 | date = July 1996 | pmid = 8649497 | doi = 10.1056/nejm199607113350206 }}</ref>  Many patients report a family history of autoimmune thyroiditis or [[Graves' disease]].<ref name="Singh2020"/>  The strong genetic component is borne out in studies on [[monozygotic twins]],<ref name="Mincer2022" /> with a [[Concordance (genetics)|concordance]] of 38–55%, with an even higher concordance of circulating thyroid antibodies not in relation to [[clinical presentation]] (up to 80% in monozygotic twins). Neither result was seen to a similar degree in [[dizygotic twins]], offering strong favour for high genetic [[etiology]].<ref name="Chistiakov-2005" />

The genes implicated vary in different ethnic groups<ref name="Jacobson-2008" /> and the impact of these genes on the disease differs significantly among people from different ethnic groups. A gene that has a large effect in one ethnic group's risk of developing Hashimoto's thyroiditis might have a much smaller effect in another ethnic group.<ref name="Chistiakov-2005" /> 

The incidence of autoimmune thyroid disorders is increased in people with [[chromosomal disorders]], including [[Turner syndrome|Turner]], [[Down syndrome|Down]], and [[Klinefelter syndrome]]s.<ref name="Casto-2021" />

==== HLA genes ====
The first gene [[Locus (genetics)|locus]] associated with autoimmune thyroid disease was the [[major histocompatibility complex]] (MHC) region on [[chromosome]] 6p21. It encodes [[human leukocyte antigen]]s (HLAs). Specific HLA [[Allele|alleles]] have a higher affinity to auto-antigenic thyroidal [[Peptide|peptides]] and can contribute to autoimmune thyroid disease development. Specifically, in Hashimoto's disease, aberrant expression of HLA II on [[Thyroid follicular cell|thyrocytes]] has been demonstrated. They can present thyroid autoantigens and initiate autoimmune thyroid disease.<ref name="Jacobson-2008">{{cite journal | vauthors = Jacobson EM, Huber A, Tomer Y | title = The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology | journal = Journal of Autoimmunity | volume = 30 | issue = 1–2 | pages = 58–62 | date = 2008 | pmid = 18178059 | pmc = 2244911 | doi = 10.1016/j.jaut.2007.11.010 }}</ref> Susceptibility alleles are not consistent in Hashimoto's disease. In Caucasians, various alleles are reported to be associated with the disease, including [[Death receptor 3|DR3]], [[Death receptor 5|DR5]], and [[HLA-DQ7|DQ7]].<ref>{{cite journal | vauthors = Tandon N, Zhang L, Weetman AP | title = HLA associations with Hashimoto's thyroiditis | journal = Clinical Endocrinology | volume = 34 | issue = 5 | pages = 383–386 | date = May 1991 | pmid = 1676351 | doi = 10.1111/j.1365-2265.1991.tb00309.x | s2cid = 28987581 }}</ref><ref>{{cite journal | vauthors = Bogner U, Badenhoop K, Peters H, Schmieg D, Mayr WR, Usadel KH, Schleusener H | title = HLA-DR/DQ gene variation in nongoitrous autoimmune thyroiditis at the serological and molecular level | journal = Autoimmunity | volume = 14 | issue = 2 | pages = 155–158 | date = January 1992 | pmid = 1363895 | doi = 10.3109/08916939209083135 }}</ref>

==== CTLA-4 genes ====
[[CTLA-4]] is the second major immune-[[Regulator gene|regulatory]] gene related to autoimmune thyroid disease. CTLA-4 gene polymorphisms may contribute to the reduced inhibition of T-cell [[Cell proliferation|proliferation]] and increase susceptibility to autoimmune response.<ref>{{cite journal | vauthors = Zaletel K, Gaberšček S | title = Hashimoto's Thyroiditis: From Genes to the Disease | journal = Current Genomics | volume = 12 | issue = 8 | pages = 576–588 | date = December 2011 | pmid = 22654557 | pmc = 3271310 | doi = 10.2174/138920211798120763 }}</ref> CTLA-4 is a major thyroid autoantibody susceptibility gene. A linkage of the CTLA-4 region to the presence of thyroid autoantibodies was demonstrated by a whole-genome [[linkage analysis]].<ref>{{cite journal | vauthors = Tomer Y, Greenberg DA, Barbesino G, Concepcion E, Davies TF | title = CTLA-4 and not CD28 is a susceptibility gene for thyroid autoantibody production | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 4 | pages = 1687–1693 | date = April 2001 | pmid = 11297604 | doi = 10.1210/jcem.86.4.7372 | doi-access = free }}</ref> CTLA-4 was confirmed as the main locus for thyroid autoantibodies.<ref>{{cite journal | vauthors = Ban Y, Davies TF, Greenberg DA, Kissin A, Marder B, Murphy B, Concepcion ES, Villanueva RB, Barbesino G, Ling V, Tomer Y | title = Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease | journal = Genes and Immunity | volume = 4 | issue = 8 | pages = 586–593 | date = December 2003 | pmid = 14647199 | doi = 10.1038/sj.gene.6364018 | s2cid = 6920190 | doi-access =  }}</ref>

====PTPN22 gene====
''[[PTPN22]]'' is the most recently identified immune-regulatory gene associated with autoimmune thyroid disease. It is located on chromosome 1p13 and expressed in lymphocytes. It acts as a negative regulator of T-cell activation. [[Mutation]] in this gene is a risk factor for many autoimmune diseases. Weaker T-cell signaling may lead to impaired [[Negative selection (immunology)|thymic deletion]] of autoreactive T cells, and increased PTPN22 function may result in inhibition of regulatory T cells, which protect against autoimmunity.<ref>{{cite journal | vauthors = Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP | title = Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? | journal = FEBS Letters | volume = 585 | issue = 23 | pages = 3689–3698 | date = December 2011 | pmid = 21515266 | doi = 10.1016/j.febslet.2011.04.032 | s2cid = 21572847 | doi-access = free | bibcode = 2011FEBSL.585.3689B }}</ref>

==== Immune-related genes ====
[[IFN-γ]] promotes cell-mediated [[cytotoxicity]] against thyroid mutations causing increased production of IFN-γ were associated with the severity of hypothyroidism.<ref>{{cite journal | vauthors = Ito C, Watanabe M, Okuda N, Watanabe C, Iwatani Y | title = Association between the severity of Hashimoto's disease and the functional +874A/T polymorphism in the interferon-gamma gene | journal = Endocrine Journal | volume = 53 | issue = 4 | pages = 473–478 | date = August 2006 | pmid = 16820703 | doi = 10.1507/endocrj.k06-015 | doi-access = free }}</ref> Severe hypothyroidism is associated with mutations leading to lower production of [[Interleukin 4|IL-4]] (Th2 cytokine suppressing cell-mediated autoimmunity),<ref>{{cite journal | vauthors = Nanba T, Watanabe M, Akamizu T, Iwatani Y | title = The -590CC genotype in the IL4 gene as a strong predictive factor for the development of hypothyroidism in Hashimoto disease | journal = Clinical Chemistry | volume = 54 | issue = 3 | pages = 621–623 | date = March 2008 | pmid = 18310157 | doi = 10.1373/clinchem.2007.099739 | doi-access =  }}</ref> lower secretion of [[TGF-β]] (inhibitor of [[cytokine]] production),<ref>{{cite journal | vauthors = Yamada H, Watanabe M, Nanba T, Akamizu T, Iwatani Y | title = The +869T/C polymorphism in the transforming growth factor-beta1 gene is associated with the severity and intractability of autoimmune thyroid disease | journal = Clinical and Experimental Immunology | volume = 151 | issue = 3 | pages = 379–382 | date = March 2008 | pmid = 18190611 | pmc = 2276968 | doi = 10.1111/j.1365-2249.2007.03575.x }}</ref> and mutations of [[FOXP3]], an essential regulatory factor for the [[regulatory T cells]] (Tregs) development.<ref>{{cite journal | vauthors = Inoue N, Watanabe M, Morita M, Tomizawa R, Akamizu T, Tatsumi K, Hidaka Y, Iwatani Y | title = Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases | journal = Clinical and Experimental Immunology | volume = 162 | issue = 3 | pages = 402–406 | date = December 2010 | pmid = 20942809 | pmc = 3026543 | doi = 10.1111/j.1365-2249.2010.04229.x }}</ref> Development of Hashimoto's disease was associated with mutation of the gene for [[TNF-α]] (stimulator of the IFN-γ production), causing its higher concentration.<ref>{{cite journal | vauthors = Inoue N, Watanabe M, Nanba T, Wada M, Akamizu T, Iwatani Y | title = Involvement of functional polymorphisms in the TNFA gene in the pathogenesis of autoimmune thyroid diseases and production of anti-thyrotropin receptor antibody | journal = Clinical and Experimental Immunology | volume = 156 | issue = 2 | pages = 199–204 | date = May 2009 | pmid = 19250279 | pmc = 2759465 | doi = 10.1111/j.1365-2249.2009.03884.x }}</ref>