The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age
Aims/hypothesis The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease proce...
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| Veröffentlicht in: | Diabetologia 2018-01, Vol.61 (1), p.147-157 |
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| creator | Inshaw, Jamie R. J. Walker, Neil M. Wallace, Chris Bottolo, Leonardo Todd, John A. |
| description | Aims/hypothesis
The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process.
Methods
Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD.
Results
Two regions were convincingly associated with AAD (
p
0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (
p
= 2.3 × 10
−9
).
Conclusion/interpretation
PTPRK
and its neighbour
THEMIS
are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant. |
| doi_str_mv | 10.1007/s00125-017-4440-y |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5719131</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1948757109</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-6afc7f3242519a4004d33a45adc1af94175e311701a8d7e78a14f2284838e7a93</originalsourceid><addsrcrecordid>eNp1kc9u1DAQxiMEokvhAbggS1y4pHhsZ-1ckFDFP6kSlyJxs6bJJHHZ2Fs7AeUleAaehSfDYZeqIHGyxvP7vpnRVxRPgZ8B5_pl4hxEVXLQpVKKl8u9YgNKipIrYe4Xm7Vdgtl-PikepXTNOZeV2j4sToSpjdRSb4rvlwOxZohhDCmMxLY3QpxJySL1LnjmEsOUQuNwopZ9c9PAsCeGE2sd9j6kDISOTcueGKx_VzRR1vg2F4kwEYsufWHOs2kIuTrKstnsW4qs-vljIYy_XbLz4-JBh7tET47vafHp7ZvL8_flxcd3H85fX5SN0nwqt9g1upNCiQpqVJyrVkpUFbYNYFcr0BVJAM0BTatJGwTVCWGUkYY01vK0eHXw3c9XI7UN-Snizu6jGzEuNqCzf3e8G2wfvtpKQw0SssGLo0EMNzOlyY4uNbTboacwJwu1MjrDfJ31_B_0OszR5_MypaVUSkiVKThQTQwpRepulwFu17TtIW2b07Zr2nbJmmd3r7hV_Ik3A-IApNzyPcU7o__r-gvTTrZp</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1973344234</pqid></control><display><type>article</type><title>The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Inshaw, Jamie R. J. ; Walker, Neil M. ; Wallace, Chris ; Bottolo, Leonardo ; Todd, John A.</creator><creatorcontrib>Inshaw, Jamie R. J. ; Walker, Neil M. ; Wallace, Chris ; Bottolo, Leonardo ; Todd, John A.</creatorcontrib><description>Aims/hypothesis
The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process.
Methods
Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD.
Results
Two regions were convincingly associated with AAD (
p
< 5 × 10
−8
): the MHC on 6p21, and 6q22.33. Fine-mapping of 6q22.33 identified two AAD-associated haplotypes in the region nearest to the genes encoding protein tyrosine phosphatase receptor kappa (
PTPRK
) and thymocyte-expressed molecule involved in selection (
THEMIS
). We examined the susceptibility to type 1 diabetes at these SNPs by performing a meta-analysis including 19,510 control participants. Although these SNPs were not associated with type 1 diabetes overall (
p
> 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (
p
= 2.3 × 10
−9
).
Conclusion/interpretation
PTPRK
and its neighbour
THEMIS
are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-017-4440-y</identifier><identifier>PMID: 28983737</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adult ; Age ; Autoimmunity ; Chromosome 6 ; Chromosomes - genetics ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 1 - diagnosis ; Diabetes Mellitus, Type 1 - genetics ; Diagnosis ; Early Diagnosis ; Female ; Gene mapping ; Genetic Predisposition to Disease - genetics ; Haplotypes ; Haplotypes - genetics ; Health risk assessment ; Histocompatibility antigen HLA ; Human Physiology ; Humans ; Internal Medicine ; Major histocompatibility complex ; Male ; Medical diagnosis ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Middle Aged ; Polymorphism, Single Nucleotide - genetics ; Protein-tyrosine-phosphatase ; Risk factors ; Single-nucleotide polymorphism ; Thymus</subject><ispartof>Diabetologia, 2018-01, Vol.61 (1), p.147-157</ispartof><rights>The Author(s) 2017</rights><rights>Diabetologia is a copyright of Springer, (2017). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-6afc7f3242519a4004d33a45adc1af94175e311701a8d7e78a14f2284838e7a93</citedby><cites>FETCH-LOGICAL-c470t-6afc7f3242519a4004d33a45adc1af94175e311701a8d7e78a14f2284838e7a93</cites><orcidid>0000-0002-7003-8966</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00125-017-4440-y$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00125-017-4440-y$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28983737$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Inshaw, Jamie R. J.</creatorcontrib><creatorcontrib>Walker, Neil M.</creatorcontrib><creatorcontrib>Wallace, Chris</creatorcontrib><creatorcontrib>Bottolo, Leonardo</creatorcontrib><creatorcontrib>Todd, John A.</creatorcontrib><title>The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><addtitle>Diabetologia</addtitle><description>Aims/hypothesis
The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process.
Methods
Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD.
Results
Two regions were convincingly associated with AAD (
p
< 5 × 10
−8
): the MHC on 6p21, and 6q22.33. Fine-mapping of 6q22.33 identified two AAD-associated haplotypes in the region nearest to the genes encoding protein tyrosine phosphatase receptor kappa (
PTPRK
) and thymocyte-expressed molecule involved in selection (
THEMIS
). We examined the susceptibility to type 1 diabetes at these SNPs by performing a meta-analysis including 19,510 control participants. Although these SNPs were not associated with type 1 diabetes overall (
p
> 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (
p
= 2.3 × 10
−9
).
Conclusion/interpretation
PTPRK
and its neighbour
THEMIS
are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant.</description><subject>Adult</subject><subject>Age</subject><subject>Autoimmunity</subject><subject>Chromosome 6</subject><subject>Chromosomes - genetics</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 1 - diagnosis</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diagnosis</subject><subject>Early Diagnosis</subject><subject>Female</subject><subject>Gene mapping</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Haplotypes</subject><subject>Haplotypes - genetics</subject><subject>Health risk assessment</subject><subject>Histocompatibility antigen HLA</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Major histocompatibility complex</subject><subject>Male</subject><subject>Medical diagnosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Middle Aged</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Protein-tyrosine-phosphatase</subject><subject>Risk factors</subject><subject>Single-nucleotide polymorphism</subject><subject>Thymus</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kc9u1DAQxiMEokvhAbggS1y4pHhsZ-1ckFDFP6kSlyJxs6bJJHHZ2Fs7AeUleAaehSfDYZeqIHGyxvP7vpnRVxRPgZ8B5_pl4hxEVXLQpVKKl8u9YgNKipIrYe4Xm7Vdgtl-PikepXTNOZeV2j4sToSpjdRSb4rvlwOxZohhDCmMxLY3QpxJySL1LnjmEsOUQuNwopZ9c9PAsCeGE2sd9j6kDISOTcueGKx_VzRR1vg2F4kwEYsufWHOs2kIuTrKstnsW4qs-vljIYy_XbLz4-JBh7tET47vafHp7ZvL8_flxcd3H85fX5SN0nwqt9g1upNCiQpqVJyrVkpUFbYNYFcr0BVJAM0BTatJGwTVCWGUkYY01vK0eHXw3c9XI7UN-Snizu6jGzEuNqCzf3e8G2wfvtpKQw0SssGLo0EMNzOlyY4uNbTboacwJwu1MjrDfJ31_B_0OszR5_MypaVUSkiVKThQTQwpRepulwFu17TtIW2b07Zr2nbJmmd3r7hV_Ik3A-IApNzyPcU7o__r-gvTTrZp</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Inshaw, Jamie R. J.</creator><creator>Walker, Neil M.</creator><creator>Wallace, Chris</creator><creator>Bottolo, Leonardo</creator><creator>Todd, John A.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7003-8966</orcidid></search><sort><creationdate>20180101</creationdate><title>The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age</title><author>Inshaw, Jamie R. J. ; Walker, Neil M. ; Wallace, Chris ; Bottolo, Leonardo ; Todd, John A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-6afc7f3242519a4004d33a45adc1af94175e311701a8d7e78a14f2284838e7a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Age</topic><topic>Autoimmunity</topic><topic>Chromosome 6</topic><topic>Chromosomes - genetics</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 1 - diagnosis</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Diagnosis</topic><topic>Early Diagnosis</topic><topic>Female</topic><topic>Gene mapping</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Haplotypes</topic><topic>Haplotypes - genetics</topic><topic>Health risk assessment</topic><topic>Histocompatibility antigen HLA</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Major histocompatibility complex</topic><topic>Male</topic><topic>Medical diagnosis</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Diseases</topic><topic>Middle Aged</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Protein-tyrosine-phosphatase</topic><topic>Risk factors</topic><topic>Single-nucleotide polymorphism</topic><topic>Thymus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Inshaw, Jamie R. J.</creatorcontrib><creatorcontrib>Walker, Neil M.</creatorcontrib><creatorcontrib>Wallace, Chris</creatorcontrib><creatorcontrib>Bottolo, Leonardo</creatorcontrib><creatorcontrib>Todd, John A.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Inshaw, Jamie R. J.</au><au>Walker, Neil M.</au><au>Wallace, Chris</au><au>Bottolo, Leonardo</au><au>Todd, John A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age</atitle><jtitle>Diabetologia</jtitle><stitle>Diabetologia</stitle><addtitle>Diabetologia</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>61</volume><issue>1</issue><spage>147</spage><epage>157</epage><pages>147-157</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>Aims/hypothesis
The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process.
Methods
Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD.
Results
Two regions were convincingly associated with AAD (
p
< 5 × 10
−8
): the MHC on 6p21, and 6q22.33. Fine-mapping of 6q22.33 identified two AAD-associated haplotypes in the region nearest to the genes encoding protein tyrosine phosphatase receptor kappa (
PTPRK
) and thymocyte-expressed molecule involved in selection (
THEMIS
). We examined the susceptibility to type 1 diabetes at these SNPs by performing a meta-analysis including 19,510 control participants. Although these SNPs were not associated with type 1 diabetes overall (
p
> 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (
p
= 2.3 × 10
−9
).
Conclusion/interpretation
PTPRK
and its neighbour
THEMIS
are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>28983737</pmid><doi>10.1007/s00125-017-4440-y</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-7003-8966</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Diabetologia, 2018-01, Vol.61 (1), p.147-157 |
| issn | 0012-186X 1432-0428 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5719131 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adult Age Autoimmunity Chromosome 6 Chromosomes - genetics Diabetes Diabetes mellitus Diabetes Mellitus, Type 1 - diagnosis Diabetes Mellitus, Type 1 - genetics Diagnosis Early Diagnosis Female Gene mapping Genetic Predisposition to Disease - genetics Haplotypes Haplotypes - genetics Health risk assessment Histocompatibility antigen HLA Human Physiology Humans Internal Medicine Major histocompatibility complex Male Medical diagnosis Medicine Medicine & Public Health Metabolic Diseases Middle Aged Polymorphism, Single Nucleotide - genetics Protein-tyrosine-phosphatase Risk factors Single-nucleotide polymorphism Thymus |
| title | The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age |
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