Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study
Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. We performed the first two-stage GWAS of T1D usi...
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| Veröffentlicht in: | Diabetes care 2019-08, Vol.42 (8), p.1414-1421 |
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| creator | Zhu, Meng Xu, Kuanfeng Chen, Yang Gu, Yong Zhang, Mei Luo, Feihong Liu, Yu Gu, Wei Hu, Ji Xu, Haixia Xie, Zhiguo Sun, Chengjun Li, Yuxiu Sun, Min Xu, Xinyu Hsu, Hsiang-Ting Chen, Heng Fu, Qi Shi, Yun Xu, Jingjing Ji, Li Liu, Jin Bian, Lingling Zhu, Jing Chen, Shuang Xiao, Lei Li, Xin Jiang, Hemin Shen, Min Huang, Qianwen Fang, Chen Li, Xia Huang, Gan Fan, Jingyi Jiang, Zhu Jiang, Yue Dai, Juncheng Ma, Hongxia Zheng, Shuai Cai, Yun Dai, Hao Zheng, Xuqin Zhou, Hongwen Ni, Shining Jin, Guangfu She, Jin-Xiong Yu, Liping Polychronakos, Constantin Hu, Zhibin Zhou, Zhiguang Weng, Jianping Shen, Hongbing Yang, Tao |
| description | Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians.
We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis.
We observed a high genetic correlation between children/adolescents and adult T1D case subjects (
= 0.87), as well as subgroups of autoantibody status (
≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near
(odds ratio [OR] 1.26,
= 2.70 × 10
) and rs3802604 in
(OR 1.24,
= 2.06 × 10
), and two previously reported loci, rs1770 in MHC (OR 4.28,
= 2.25 × 10
) and rs705699 in
(OR 1.46,
= 7.48 × 10
). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus
= 9.78 × 10
), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (
= 9.08 × 10
) and lower fasting C-peptide levels (
= 7.19 × 10
) in individuals newly diagnosed with T1D.
Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine. |
| doi_str_mv | 10.2337/dc18-2023 |
| format | Article |
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We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis.
We observed a high genetic correlation between children/adolescents and adult T1D case subjects (
= 0.87), as well as subgroups of autoantibody status (
≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near
(odds ratio [OR] 1.26,
= 2.70 × 10
) and rs3802604 in
(OR 1.24,
= 2.06 × 10
), and two previously reported loci, rs1770 in MHC (OR 4.28,
= 2.25 × 10
) and rs705699 in
(OR 1.46,
= 7.48 × 10
). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus
= 9.78 × 10
), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (
= 9.08 × 10
) and lower fasting C-peptide levels (
= 7.19 × 10
) in individuals newly diagnosed with T1D.
Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.</description><identifier>ISSN: 0149-5992</identifier><identifier>EISSN: 1935-5548</identifier><identifier>DOI: 10.2337/dc18-2023</identifier><identifier>PMID: 31152121</identifier><language>eng</language><publisher>United States: American Diabetes Association</publisher><subject>Adolescent ; Adolescents ; Adult ; Age ; Age Factors ; Antigens, CD - genetics ; Asian Continental Ancestry Group - genetics ; Autoantibodies ; Autoantibodies - blood ; Butyrophilins - genetics ; C-Peptide - blood ; Child ; Children ; China ; Diabetes mellitus ; Diabetes mellitus (insulin dependent) ; Diabetes Mellitus, Type 1 - blood ; Diabetes Mellitus, Type 1 - genetics ; Diabetes Mellitus, Type 1 - immunology ; Diagnosis ; Fasting ; Fasting - blood ; Female ; GATA-3 protein ; GATA3 Transcription Factor - genetics ; Gene mapping ; Genetic Loci - genetics ; Genome-Wide Association Study ; Genomes ; Heterogeneity ; Histocompatibility Antigens Class I - genetics ; Humans ; Loci ; Major histocompatibility complex ; Male ; Mapping ; Medical diagnosis ; Odds Ratio ; Oxidoreductases Acting on Sulfur Group Donors - genetics ; Peptides ; Population ; Population genetics ; Population studies ; Precision medicine ; Research design ; Risk ; Risk Factors ; Subgroups</subject><ispartof>Diabetes care, 2019-08, Vol.42 (8), p.1414-1421</ispartof><rights>2019 by the American Diabetes Association.</rights><rights>Copyright American Diabetes Association Aug 1, 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c348t-3269b43b8c9eedb30f408c0eca25d21427a94ae2d5a6b971e919e9696886ca353</citedby><cites>FETCH-LOGICAL-c348t-3269b43b8c9eedb30f408c0eca25d21427a94ae2d5a6b971e919e9696886ca353</cites><orcidid>0000-0002-7624-6635 ; 0000-0001-6375-3622 ; 0000-0003-0664-2154 ; 0000-0003-0227-4323 ; 0000-0002-0374-1838 ; 0000-0003-2705-196X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31152121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhu, Meng</creatorcontrib><creatorcontrib>Xu, Kuanfeng</creatorcontrib><creatorcontrib>Chen, Yang</creatorcontrib><creatorcontrib>Gu, Yong</creatorcontrib><creatorcontrib>Zhang, Mei</creatorcontrib><creatorcontrib>Luo, Feihong</creatorcontrib><creatorcontrib>Liu, Yu</creatorcontrib><creatorcontrib>Gu, Wei</creatorcontrib><creatorcontrib>Hu, Ji</creatorcontrib><creatorcontrib>Xu, Haixia</creatorcontrib><creatorcontrib>Xie, Zhiguo</creatorcontrib><creatorcontrib>Sun, Chengjun</creatorcontrib><creatorcontrib>Li, Yuxiu</creatorcontrib><creatorcontrib>Sun, Min</creatorcontrib><creatorcontrib>Xu, Xinyu</creatorcontrib><creatorcontrib>Hsu, Hsiang-Ting</creatorcontrib><creatorcontrib>Chen, Heng</creatorcontrib><creatorcontrib>Fu, Qi</creatorcontrib><creatorcontrib>Shi, Yun</creatorcontrib><creatorcontrib>Xu, Jingjing</creatorcontrib><creatorcontrib>Ji, Li</creatorcontrib><creatorcontrib>Liu, Jin</creatorcontrib><creatorcontrib>Bian, Lingling</creatorcontrib><creatorcontrib>Zhu, Jing</creatorcontrib><creatorcontrib>Chen, Shuang</creatorcontrib><creatorcontrib>Xiao, Lei</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Jiang, Hemin</creatorcontrib><creatorcontrib>Shen, Min</creatorcontrib><creatorcontrib>Huang, Qianwen</creatorcontrib><creatorcontrib>Fang, Chen</creatorcontrib><creatorcontrib>Li, Xia</creatorcontrib><creatorcontrib>Huang, Gan</creatorcontrib><creatorcontrib>Fan, Jingyi</creatorcontrib><creatorcontrib>Jiang, Zhu</creatorcontrib><creatorcontrib>Jiang, Yue</creatorcontrib><creatorcontrib>Dai, Juncheng</creatorcontrib><creatorcontrib>Ma, Hongxia</creatorcontrib><creatorcontrib>Zheng, Shuai</creatorcontrib><creatorcontrib>Cai, Yun</creatorcontrib><creatorcontrib>Dai, Hao</creatorcontrib><creatorcontrib>Zheng, Xuqin</creatorcontrib><creatorcontrib>Zhou, Hongwen</creatorcontrib><creatorcontrib>Ni, Shining</creatorcontrib><creatorcontrib>Jin, Guangfu</creatorcontrib><creatorcontrib>She, Jin-Xiong</creatorcontrib><creatorcontrib>Yu, Liping</creatorcontrib><creatorcontrib>Polychronakos, Constantin</creatorcontrib><creatorcontrib>Hu, Zhibin</creatorcontrib><creatorcontrib>Zhou, Zhiguang</creatorcontrib><creatorcontrib>Weng, Jianping</creatorcontrib><creatorcontrib>Shen, Hongbing</creatorcontrib><creatorcontrib>Yang, Tao</creatorcontrib><title>Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study</title><title>Diabetes care</title><addtitle>Diabetes Care</addtitle><description>Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians.
We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis.
We observed a high genetic correlation between children/adolescents and adult T1D case subjects (
= 0.87), as well as subgroups of autoantibody status (
≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near
(odds ratio [OR] 1.26,
= 2.70 × 10
) and rs3802604 in
(OR 1.24,
= 2.06 × 10
), and two previously reported loci, rs1770 in MHC (OR 4.28,
= 2.25 × 10
) and rs705699 in
(OR 1.46,
= 7.48 × 10
). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus
= 9.78 × 10
), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (
= 9.08 × 10
) and lower fasting C-peptide levels (
= 7.19 × 10
) in individuals newly diagnosed with T1D.
Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.</description><subject>Adolescent</subject><subject>Adolescents</subject><subject>Adult</subject><subject>Age</subject><subject>Age Factors</subject><subject>Antigens, CD - genetics</subject><subject>Asian Continental Ancestry Group - genetics</subject><subject>Autoantibodies</subject><subject>Autoantibodies - blood</subject><subject>Butyrophilins - genetics</subject><subject>C-Peptide - blood</subject><subject>Child</subject><subject>Children</subject><subject>China</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (insulin dependent)</subject><subject>Diabetes Mellitus, Type 1 - blood</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Diagnosis</subject><subject>Fasting</subject><subject>Fasting - blood</subject><subject>Female</subject><subject>GATA-3 protein</subject><subject>GATA3 Transcription Factor - genetics</subject><subject>Gene mapping</subject><subject>Genetic Loci - genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Heterogeneity</subject><subject>Histocompatibility Antigens Class I - genetics</subject><subject>Humans</subject><subject>Loci</subject><subject>Major histocompatibility complex</subject><subject>Male</subject><subject>Mapping</subject><subject>Medical diagnosis</subject><subject>Odds Ratio</subject><subject>Oxidoreductases Acting on Sulfur Group Donors - genetics</subject><subject>Peptides</subject><subject>Population</subject><subject>Population genetics</subject><subject>Population studies</subject><subject>Precision medicine</subject><subject>Research design</subject><subject>Risk</subject><subject>Risk Factors</subject><subject>Subgroups</subject><issn>0149-5992</issn><issn>1935-5548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1uEzEURi0EomlhwQsgS2xgYfDfzNjsQktLpAgQDepy5LHvtC4Tu4w9qfJ4vBlOUpBgZenec7_P0kHoBaNvuRDNO2eZIpxy8QjNmBYVqSqpHqMZZVKTSmt-hI5TuqWUSqnUU3QkGKs442yGfi0chOx7b032MeDY489xAwNesTP8zacfeBmtxyY4vLoBP-J5SmVwgK98vsHza9ivF2mAjM-nYPc7k_GZN9chJp-wD3g-5WhKUxfdlnwt0-w3sG9ZBOc33k1mSO_xB5PA4d09Xt1HcplNib-AENdArryDf_ov8-S2z9CTvpzC84f3BH0__7g6_USWXy4Wp_MlsUKqTASvdSdFp6wGcJ2gvaTKUrCGV44zyRujpQHuKlN3umGgmQZd61qp2hpRiRP0-pB7N8afE6Tcrn2yMAwmQJxSy4sKJVXN6oK--g-9jdMYyu8K1QimdCNZod4cKDvGlEbo27vRr824bRltd17bndd257WwLx8Sp24N7i_5R6T4DbyKncA</recordid><startdate>201908</startdate><enddate>201908</enddate><creator>Zhu, Meng</creator><creator>Xu, Kuanfeng</creator><creator>Chen, Yang</creator><creator>Gu, Yong</creator><creator>Zhang, Mei</creator><creator>Luo, Feihong</creator><creator>Liu, Yu</creator><creator>Gu, Wei</creator><creator>Hu, Ji</creator><creator>Xu, Haixia</creator><creator>Xie, Zhiguo</creator><creator>Sun, Chengjun</creator><creator>Li, Yuxiu</creator><creator>Sun, Min</creator><creator>Xu, Xinyu</creator><creator>Hsu, Hsiang-Ting</creator><creator>Chen, Heng</creator><creator>Fu, Qi</creator><creator>Shi, Yun</creator><creator>Xu, Jingjing</creator><creator>Ji, Li</creator><creator>Liu, Jin</creator><creator>Bian, Lingling</creator><creator>Zhu, Jing</creator><creator>Chen, Shuang</creator><creator>Xiao, Lei</creator><creator>Li, Xin</creator><creator>Jiang, Hemin</creator><creator>Shen, Min</creator><creator>Huang, Qianwen</creator><creator>Fang, Chen</creator><creator>Li, Xia</creator><creator>Huang, Gan</creator><creator>Fan, Jingyi</creator><creator>Jiang, Zhu</creator><creator>Jiang, Yue</creator><creator>Dai, Juncheng</creator><creator>Ma, Hongxia</creator><creator>Zheng, Shuai</creator><creator>Cai, 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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><orcidid>https://orcid.org/0000-0002-7624-6635</orcidid><orcidid>https://orcid.org/0000-0001-6375-3622</orcidid><orcidid>https://orcid.org/0000-0003-0664-2154</orcidid><orcidid>https://orcid.org/0000-0003-0227-4323</orcidid><orcidid>https://orcid.org/0000-0002-0374-1838</orcidid><orcidid>https://orcid.org/0000-0003-2705-196X</orcidid></search><sort><creationdate>201908</creationdate><title>Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study</title><author>Zhu, Meng ; Xu, Kuanfeng ; Chen, Yang ; Gu, Yong ; Zhang, Mei ; Luo, Feihong ; Liu, Yu ; Gu, Wei ; Hu, Ji ; Xu, Haixia ; Xie, Zhiguo ; Sun, Chengjun ; Li, Yuxiu ; Sun, Min ; Xu, Xinyu ; Hsu, Hsiang-Ting ; Chen, Heng ; Fu, Qi ; Shi, Yun ; Xu, Jingjing ; Ji, Li ; Liu, Jin ; Bian, Lingling ; Zhu, Jing ; Chen, Shuang ; Xiao, Lei ; Li, Xin ; Jiang, Hemin ; Shen, Min ; Huang, Qianwen ; Fang, Chen ; Li, Xia ; Huang, Gan ; Fan, Jingyi ; Jiang, Zhu ; Jiang, Yue ; Dai, Juncheng ; Ma, Hongxia ; Zheng, Shuai ; Cai, Yun ; Dai, Hao ; Zheng, Xuqin ; Zhou, Hongwen ; Ni, Shining ; Jin, Guangfu ; She, Jin-Xiong ; Yu, Liping ; Polychronakos, Constantin ; Hu, Zhibin ; Zhou, Zhiguang ; Weng, Jianping ; Shen, Hongbing ; Yang, Tao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c348t-3269b43b8c9eedb30f408c0eca25d21427a94ae2d5a6b971e919e9696886ca353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adolescent</topic><topic>Adolescents</topic><topic>Adult</topic><topic>Age</topic><topic>Age Factors</topic><topic>Antigens, CD - genetics</topic><topic>Asian Continental Ancestry Group - genetics</topic><topic>Autoantibodies</topic><topic>Autoantibodies - blood</topic><topic>Butyrophilins - genetics</topic><topic>C-Peptide - blood</topic><topic>Child</topic><topic>Children</topic><topic>China</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (insulin dependent)</topic><topic>Diabetes Mellitus, Type 1 - blood</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>Diagnosis</topic><topic>Fasting</topic><topic>Fasting - blood</topic><topic>Female</topic><topic>GATA-3 protein</topic><topic>GATA3 Transcription Factor - genetics</topic><topic>Gene mapping</topic><topic>Genetic Loci - genetics</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Heterogeneity</topic><topic>Histocompatibility Antigens Class I - genetics</topic><topic>Humans</topic><topic>Loci</topic><topic>Major histocompatibility complex</topic><topic>Male</topic><topic>Mapping</topic><topic>Medical diagnosis</topic><topic>Odds Ratio</topic><topic>Oxidoreductases Acting on Sulfur Group Donors - genetics</topic><topic>Peptides</topic><topic>Population</topic><topic>Population genetics</topic><topic>Population studies</topic><topic>Precision medicine</topic><topic>Research design</topic><topic>Risk</topic><topic>Risk Factors</topic><topic>Subgroups</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhu, Meng</creatorcontrib><creatorcontrib>Xu, Kuanfeng</creatorcontrib><creatorcontrib>Chen, Yang</creatorcontrib><creatorcontrib>Gu, Yong</creatorcontrib><creatorcontrib>Zhang, Mei</creatorcontrib><creatorcontrib>Luo, Feihong</creatorcontrib><creatorcontrib>Liu, Yu</creatorcontrib><creatorcontrib>Gu, Wei</creatorcontrib><creatorcontrib>Hu, Ji</creatorcontrib><creatorcontrib>Xu, Haixia</creatorcontrib><creatorcontrib>Xie, Zhiguo</creatorcontrib><creatorcontrib>Sun, Chengjun</creatorcontrib><creatorcontrib>Li, Yuxiu</creatorcontrib><creatorcontrib>Sun, Min</creatorcontrib><creatorcontrib>Xu, Xinyu</creatorcontrib><creatorcontrib>Hsu, Hsiang-Ting</creatorcontrib><creatorcontrib>Chen, Heng</creatorcontrib><creatorcontrib>Fu, Qi</creatorcontrib><creatorcontrib>Shi, Yun</creatorcontrib><creatorcontrib>Xu, Jingjing</creatorcontrib><creatorcontrib>Ji, Li</creatorcontrib><creatorcontrib>Liu, Jin</creatorcontrib><creatorcontrib>Bian, Lingling</creatorcontrib><creatorcontrib>Zhu, Jing</creatorcontrib><creatorcontrib>Chen, Shuang</creatorcontrib><creatorcontrib>Xiao, Lei</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Jiang, Hemin</creatorcontrib><creatorcontrib>Shen, Min</creatorcontrib><creatorcontrib>Huang, Qianwen</creatorcontrib><creatorcontrib>Fang, Chen</creatorcontrib><creatorcontrib>Li, Xia</creatorcontrib><creatorcontrib>Huang, Gan</creatorcontrib><creatorcontrib>Fan, Jingyi</creatorcontrib><creatorcontrib>Jiang, Zhu</creatorcontrib><creatorcontrib>Jiang, Yue</creatorcontrib><creatorcontrib>Dai, Juncheng</creatorcontrib><creatorcontrib>Ma, Hongxia</creatorcontrib><creatorcontrib>Zheng, Shuai</creatorcontrib><creatorcontrib>Cai, Yun</creatorcontrib><creatorcontrib>Dai, Hao</creatorcontrib><creatorcontrib>Zheng, Xuqin</creatorcontrib><creatorcontrib>Zhou, Hongwen</creatorcontrib><creatorcontrib>Ni, Shining</creatorcontrib><creatorcontrib>Jin, Guangfu</creatorcontrib><creatorcontrib>She, Jin-Xiong</creatorcontrib><creatorcontrib>Yu, Liping</creatorcontrib><creatorcontrib>Polychronakos, Constantin</creatorcontrib><creatorcontrib>Hu, Zhibin</creatorcontrib><creatorcontrib>Zhou, Zhiguang</creatorcontrib><creatorcontrib>Weng, Jianping</creatorcontrib><creatorcontrib>Shen, Hongbing</creatorcontrib><creatorcontrib>Yang, Tao</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><jtitle>Diabetes care</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhu, Meng</au><au>Xu, Kuanfeng</au><au>Chen, Yang</au><au>Gu, Yong</au><au>Zhang, Mei</au><au>Luo, Feihong</au><au>Liu, Yu</au><au>Gu, Wei</au><au>Hu, Ji</au><au>Xu, Haixia</au><au>Xie, Zhiguo</au><au>Sun, Chengjun</au><au>Li, Yuxiu</au><au>Sun, Min</au><au>Xu, Xinyu</au><au>Hsu, Hsiang-Ting</au><au>Chen, Heng</au><au>Fu, Qi</au><au>Shi, Yun</au><au>Xu, Jingjing</au><au>Ji, Li</au><au>Liu, Jin</au><au>Bian, Lingling</au><au>Zhu, Jing</au><au>Chen, Shuang</au><au>Xiao, Lei</au><au>Li, Xin</au><au>Jiang, Hemin</au><au>Shen, Min</au><au>Huang, Qianwen</au><au>Fang, Chen</au><au>Li, Xia</au><au>Huang, Gan</au><au>Fan, Jingyi</au><au>Jiang, Zhu</au><au>Jiang, Yue</au><au>Dai, Juncheng</au><au>Ma, Hongxia</au><au>Zheng, Shuai</au><au>Cai, Yun</au><au>Dai, Hao</au><au>Zheng, Xuqin</au><au>Zhou, Hongwen</au><au>Ni, Shining</au><au>Jin, Guangfu</au><au>She, Jin-Xiong</au><au>Yu, Liping</au><au>Polychronakos, Constantin</au><au>Hu, Zhibin</au><au>Zhou, Zhiguang</au><au>Weng, Jianping</au><au>Shen, Hongbing</au><au>Yang, Tao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study</atitle><jtitle>Diabetes care</jtitle><addtitle>Diabetes Care</addtitle><date>2019-08</date><risdate>2019</risdate><volume>42</volume><issue>8</issue><spage>1414</spage><epage>1421</epage><pages>1414-1421</pages><issn>0149-5992</issn><eissn>1935-5548</eissn><abstract>Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians.
We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis.
We observed a high genetic correlation between children/adolescents and adult T1D case subjects (
= 0.87), as well as subgroups of autoantibody status (
≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near
(odds ratio [OR] 1.26,
= 2.70 × 10
) and rs3802604 in
(OR 1.24,
= 2.06 × 10
), and two previously reported loci, rs1770 in MHC (OR 4.28,
= 2.25 × 10
) and rs705699 in
(OR 1.46,
= 7.48 × 10
). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus
= 9.78 × 10
), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (
= 9.08 × 10
) and lower fasting C-peptide levels (
= 7.19 × 10
) in individuals newly diagnosed with T1D.
Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.</abstract><cop>United States</cop><pub>American Diabetes Association</pub><pmid>31152121</pmid><doi>10.2337/dc18-2023</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-7624-6635</orcidid><orcidid>https://orcid.org/0000-0001-6375-3622</orcidid><orcidid>https://orcid.org/0000-0003-0664-2154</orcidid><orcidid>https://orcid.org/0000-0003-0227-4323</orcidid><orcidid>https://orcid.org/0000-0002-0374-1838</orcidid><orcidid>https://orcid.org/0000-0003-2705-196X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0149-5992 |
| ispartof | Diabetes care, 2019-08, Vol.42 (8), p.1414-1421 |
| issn | 0149-5992 1935-5548 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2233848616 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adolescent Adolescents Adult Age Age Factors Antigens, CD - genetics Asian Continental Ancestry Group - genetics Autoantibodies Autoantibodies - blood Butyrophilins - genetics C-Peptide - blood Child Children China Diabetes mellitus Diabetes mellitus (insulin dependent) Diabetes Mellitus, Type 1 - blood Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Diagnosis Fasting Fasting - blood Female GATA-3 protein GATA3 Transcription Factor - genetics Gene mapping Genetic Loci - genetics Genome-Wide Association Study Genomes Heterogeneity Histocompatibility Antigens Class I - genetics Humans Loci Major histocompatibility complex Male Mapping Medical diagnosis Odds Ratio Oxidoreductases Acting on Sulfur Group Donors - genetics Peptides Population Population genetics Population studies Precision medicine Research design Risk Risk Factors Subgroups |
| title | Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T17%3A18%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20Novel%20T1D%20Risk%20Loci%20and%20Their%20Association%20With%20Age%20and%20Islet%20Function%20at%20Diagnosis%20in%20Autoantibody-Positive%20T1D%20Individuals:%20Based%20on%20a%20Two-Stage%20Genome-Wide%20Association%20Study&rft.jtitle=Diabetes%20care&rft.au=Zhu,%20Meng&rft.date=2019-08&rft.volume=42&rft.issue=8&rft.spage=1414&rft.epage=1421&rft.pages=1414-1421&rft.issn=0149-5992&rft.eissn=1935-5548&rft_id=info:doi/10.2337/dc18-2023&rft_dat=%3Cproquest_cross%3E2273189741%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2273189741&rft_id=info:pmid/31152121&rfr_iscdi=true |