Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells
Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at
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| Veröffentlicht in: | Diabetes care 2020-01, Vol.43 (1), p.169-177 |
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| creator | Inshaw, Jamie R J Cutler, Antony J Crouch, Daniel J M Wicker, Linda S Todd, John A |
| description | Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at |
| doi_str_mv | 10.2337/dc19-0803 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6925581</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2299139543</sourcerecordid><originalsourceid>FETCH-LOGICAL-c333t-aee45f2fc0ff9d07fef2ad78cd2450592003228276b05d9fff4a474364c8624e3</originalsourceid><addsrcrecordid>eNpdks9u1DAQxiMEokvhwAugkbjAIeD4zya-IFULLZUWqNQtEqfIa4-zrhJ7aztI-1jwIDwTiVoqQD54pPn5m288UxTPK_KGMla_NbqSJWkIe1AsKslEKQRvHhYLUnFZCinpUfEkpWtCCOdN87g4YpUQjeB8Ufw4Q4_ZafiqolM-J7iIaFzah-R8B59CynCZY_Bdf4AcYHPYI1Tw3qktZkxz0PmQ0MCVNxjhpEOo4RuqmGDtED5PEayUN86ojDBXS7DZqQyno9fZBQ_OQ94hnA_D6BEuDynjANOLOXGhvI6oZoO_fpYr7Pv0tHhkVZ_w2d19XFydftisPpbrL2fnq5N1qRljuVSIXFhqNbFWGlJbtFSZutGGckGEpIQwShtaL7dEGGmt5YrXnC25bpaUIzsu3t3q7sftgEajz1H17T66QcVDG5Rr_814t2u78L1dSjr9bjUJvLoTiOFmxJTbwSU9taA8hjG1lEpZMSk4m9CX_6HXYYx-aq-dBlzVzXRm6vUtpWNIKaK9N1ORmavbeRHaeREm9sXf7u_JP5NnvwHJjbAp</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2331787873</pqid></control><display><type>article</type><title>Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Inshaw, Jamie R J ; Cutler, Antony J ; Crouch, Daniel J M ; Wicker, Linda S ; Todd, John A</creator><creatorcontrib>Inshaw, Jamie R J ; Cutler, Antony J ; Crouch, Daniel J M ; Wicker, Linda S ; Todd, John A</creatorcontrib><description><![CDATA[Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at <7 years (<7 group) and those diagnosed at age ≥13 years (≥13 group), with both B- and T-lymphocyte islet inflammation common in children in the <7 group, whereas B cells are rare in the ≥13 group. Based on these observations, we sought to identify differences in genetic susceptibility between these prespecified age-at-diagnosis groups to inform on the etiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.
Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA and 55 non-HLA loci) had significantly stronger effect sizes in the <7 group compared with the ≥13 group, using genotype data from 27,071 individuals (18,485 control subjects and 3,121 case subjects diagnosed at <7 years, 3,757 at 7-13 years, and 1,708 at ≥13 years).
Six HLA haplotypes/classical alleles and six non-HLA regions, one of which functions specifically in β-cells (
) and the other five likely affecting key T-cell (
,
,
, and
), thymus (
), and B-cell development/functions (
and
) or in both immune and β-cells (
), showed evidence for stronger effects in the <7 group.
A subset of type 1 diabetes-associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic β- and immune cells.]]></description><identifier>ISSN: 0149-5992</identifier><identifier>EISSN: 1935-5548</identifier><identifier>DOI: 10.2337/dc19-0803</identifier><identifier>PMID: 31558544</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Adolescent ; Adult ; Age ; Age of Onset ; Alleles ; Autoantibodies - genetics ; Autoantibodies - immunology ; Beta cells ; Case-Control Studies ; Child ; Child, Preschool ; Children ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (insulin dependent) ; Diabetes Mellitus, Type 1 - diagnosis ; Diabetes Mellitus, Type 1 - epidemiology ; Diabetes Mellitus, Type 1 - genetics ; Diabetes Mellitus, Type 1 - immunology ; Etiology ; Female ; Genes ; Genetic diversity ; Genetic Predisposition to Disease ; Genetic variance ; Genotype ; Genotypes ; Haplotypes ; Histocompatibility antigen HLA ; Humans ; Immune system ; Immune System - metabolism ; Infant ; Infant, Newborn ; Insulin-Secreting Cells - immunology ; Insulin-Secreting Cells - metabolism ; Insulin-Secreting Cells - pathology ; Interleukin 1 ; Interleukin 10 ; Interleukin 2 receptors ; Islets of Langerhans - immunology ; Islets of Langerhans - metabolism ; Loci ; Lymphocytes ; Lymphocytes T ; Male ; Medical diagnosis ; Middle Aged ; Pancreas ; Pathophysiology/Complications ; Polymorphism, Genetic ; Regression analysis ; Regression models ; Research design ; Young Adult</subject><ispartof>Diabetes care, 2020-01, Vol.43 (1), p.169-177</ispartof><rights>2019 by the American Diabetes Association.</rights><rights>Copyright American Diabetes Association Jan 1, 2020</rights><rights>2019 by the American Diabetes Association. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c333t-aee45f2fc0ff9d07fef2ad78cd2450592003228276b05d9fff4a474364c8624e3</citedby><cites>FETCH-LOGICAL-c333t-aee45f2fc0ff9d07fef2ad78cd2450592003228276b05d9fff4a474364c8624e3</cites><orcidid>0000-0002-7003-8966</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31558544$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Inshaw, Jamie R J</creatorcontrib><creatorcontrib>Cutler, Antony J</creatorcontrib><creatorcontrib>Crouch, Daniel J M</creatorcontrib><creatorcontrib>Wicker, Linda S</creatorcontrib><creatorcontrib>Todd, John A</creatorcontrib><title>Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells</title><title>Diabetes care</title><addtitle>Diabetes Care</addtitle><description><![CDATA[Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at <7 years (<7 group) and those diagnosed at age ≥13 years (≥13 group), with both B- and T-lymphocyte islet inflammation common in children in the <7 group, whereas B cells are rare in the ≥13 group. Based on these observations, we sought to identify differences in genetic susceptibility between these prespecified age-at-diagnosis groups to inform on the etiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.
Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA and 55 non-HLA loci) had significantly stronger effect sizes in the <7 group compared with the ≥13 group, using genotype data from 27,071 individuals (18,485 control subjects and 3,121 case subjects diagnosed at <7 years, 3,757 at 7-13 years, and 1,708 at ≥13 years).
Six HLA haplotypes/classical alleles and six non-HLA regions, one of which functions specifically in β-cells (
) and the other five likely affecting key T-cell (
,
,
, and
), thymus (
), and B-cell development/functions (
and
) or in both immune and β-cells (
), showed evidence for stronger effects in the <7 group.
A subset of type 1 diabetes-associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic β- and immune cells.]]></description><subject>Adolescent</subject><subject>Adult</subject><subject>Age</subject><subject>Age of Onset</subject><subject>Alleles</subject><subject>Autoantibodies - genetics</subject><subject>Autoantibodies - immunology</subject><subject>Beta cells</subject><subject>Case-Control Studies</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Children</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Diabetes Mellitus, Type 1 - diagnosis</subject><subject>Diabetes Mellitus, Type 1 - epidemiology</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Etiology</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic diversity</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic variance</subject><subject>Genotype</subject><subject>Genotypes</subject><subject>Haplotypes</subject><subject>Histocompatibility antigen HLA</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immune System - metabolism</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Insulin-Secreting Cells - immunology</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Insulin-Secreting Cells - pathology</subject><subject>Interleukin 1</subject><subject>Interleukin 10</subject><subject>Interleukin 2 receptors</subject><subject>Islets of Langerhans - immunology</subject><subject>Islets of Langerhans - metabolism</subject><subject>Loci</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Medical diagnosis</subject><subject>Middle Aged</subject><subject>Pancreas</subject><subject>Pathophysiology/Complications</subject><subject>Polymorphism, Genetic</subject><subject>Regression analysis</subject><subject>Regression models</subject><subject>Research design</subject><subject>Young Adult</subject><issn>0149-5992</issn><issn>1935-5548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdks9u1DAQxiMEokvhwAugkbjAIeD4zya-IFULLZUWqNQtEqfIa4-zrhJ7aztI-1jwIDwTiVoqQD54pPn5m288UxTPK_KGMla_NbqSJWkIe1AsKslEKQRvHhYLUnFZCinpUfEkpWtCCOdN87g4YpUQjeB8Ufw4Q4_ZafiqolM-J7iIaFzah-R8B59CynCZY_Bdf4AcYHPYI1Tw3qktZkxz0PmQ0MCVNxjhpEOo4RuqmGDtED5PEayUN86ojDBXS7DZqQyno9fZBQ_OQ94hnA_D6BEuDynjANOLOXGhvI6oZoO_fpYr7Pv0tHhkVZ_w2d19XFydftisPpbrL2fnq5N1qRljuVSIXFhqNbFWGlJbtFSZutGGckGEpIQwShtaL7dEGGmt5YrXnC25bpaUIzsu3t3q7sftgEajz1H17T66QcVDG5Rr_814t2u78L1dSjr9bjUJvLoTiOFmxJTbwSU9taA8hjG1lEpZMSk4m9CX_6HXYYx-aq-dBlzVzXRm6vUtpWNIKaK9N1ORmavbeRHaeREm9sXf7u_JP5NnvwHJjbAp</recordid><startdate>20200101</startdate><enddate>20200101</enddate><creator>Inshaw, Jamie R J</creator><creator>Cutler, Antony J</creator><creator>Crouch, Daniel J M</creator><creator>Wicker, Linda S</creator><creator>Todd, John A</creator><general>American Diabetes Association</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7003-8966</orcidid></search><sort><creationdate>20200101</creationdate><title>Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells</title><author>Inshaw, Jamie R J ; Cutler, Antony J ; Crouch, Daniel J M ; Wicker, Linda S ; Todd, John A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c333t-aee45f2fc0ff9d07fef2ad78cd2450592003228276b05d9fff4a474364c8624e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Age</topic><topic>Age of Onset</topic><topic>Alleles</topic><topic>Autoantibodies - genetics</topic><topic>Autoantibodies - immunology</topic><topic>Beta cells</topic><topic>Case-Control Studies</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Children</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Diabetes Mellitus, Type 1 - diagnosis</topic><topic>Diabetes Mellitus, Type 1 - epidemiology</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>Etiology</topic><topic>Female</topic><topic>Genes</topic><topic>Genetic diversity</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic variance</topic><topic>Genotype</topic><topic>Genotypes</topic><topic>Haplotypes</topic><topic>Histocompatibility antigen HLA</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immune System - metabolism</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Insulin-Secreting Cells - immunology</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Insulin-Secreting Cells - pathology</topic><topic>Interleukin 1</topic><topic>Interleukin 10</topic><topic>Interleukin 2 receptors</topic><topic>Islets of Langerhans - immunology</topic><topic>Islets of Langerhans - metabolism</topic><topic>Loci</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Medical diagnosis</topic><topic>Middle Aged</topic><topic>Pancreas</topic><topic>Pathophysiology/Complications</topic><topic>Polymorphism, Genetic</topic><topic>Regression analysis</topic><topic>Regression models</topic><topic>Research design</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Inshaw, Jamie R J</creatorcontrib><creatorcontrib>Cutler, Antony J</creatorcontrib><creatorcontrib>Crouch, Daniel J M</creatorcontrib><creatorcontrib>Wicker, Linda S</creatorcontrib><creatorcontrib>Todd, John A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes care</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Inshaw, Jamie R J</au><au>Cutler, Antony J</au><au>Crouch, Daniel J M</au><au>Wicker, Linda S</au><au>Todd, John A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells</atitle><jtitle>Diabetes care</jtitle><addtitle>Diabetes Care</addtitle><date>2020-01-01</date><risdate>2020</risdate><volume>43</volume><issue>1</issue><spage>169</spage><epage>177</epage><pages>169-177</pages><issn>0149-5992</issn><eissn>1935-5548</eissn><abstract><![CDATA[Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at <7 years (<7 group) and those diagnosed at age ≥13 years (≥13 group), with both B- and T-lymphocyte islet inflammation common in children in the <7 group, whereas B cells are rare in the ≥13 group. Based on these observations, we sought to identify differences in genetic susceptibility between these prespecified age-at-diagnosis groups to inform on the etiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.
Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA and 55 non-HLA loci) had significantly stronger effect sizes in the <7 group compared with the ≥13 group, using genotype data from 27,071 individuals (18,485 control subjects and 3,121 case subjects diagnosed at <7 years, 3,757 at 7-13 years, and 1,708 at ≥13 years).
Six HLA haplotypes/classical alleles and six non-HLA regions, one of which functions specifically in β-cells (
) and the other five likely affecting key T-cell (
,
,
, and
), thymus (
), and B-cell development/functions (
and
) or in both immune and β-cells (
), showed evidence for stronger effects in the <7 group.
A subset of type 1 diabetes-associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic β- and immune cells.]]></abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>31558544</pmid><doi>10.2337/dc19-0803</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-7003-8966</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Diabetes care, 2020-01, Vol.43 (1), p.169-177 |
| issn | 0149-5992 1935-5548 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6925581 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adolescent Adult Age Age of Onset Alleles Autoantibodies - genetics Autoantibodies - immunology Beta cells Case-Control Studies Child Child, Preschool Children Diabetes Diabetes mellitus Diabetes mellitus (insulin dependent) Diabetes Mellitus, Type 1 - diagnosis Diabetes Mellitus, Type 1 - epidemiology Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Etiology Female Genes Genetic diversity Genetic Predisposition to Disease Genetic variance Genotype Genotypes Haplotypes Histocompatibility antigen HLA Humans Immune system Immune System - metabolism Infant Infant, Newborn Insulin-Secreting Cells - immunology Insulin-Secreting Cells - metabolism Insulin-Secreting Cells - pathology Interleukin 1 Interleukin 10 Interleukin 2 receptors Islets of Langerhans - immunology Islets of Langerhans - metabolism Loci Lymphocytes Lymphocytes T Male Medical diagnosis Middle Aged Pancreas Pathophysiology/Complications Polymorphism, Genetic Regression analysis Regression models Research design Young Adult |
| title | Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells |
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