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
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
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自身抗体阳性 T1D 个体新的 T1D 风险位点的鉴定及其与诊断时年龄和胰岛功能的关联：基于两阶段全基因组关联研究
DOI：
10.2337/dc18-2023
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发表时间：
2019-05
期刊：
影响因子：
16.2
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
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 X
目的 1型糖尿病（T1D）是一种高度遗传的疾病，在中国人群中发病率低得多，但成年发病的病例更多。尽管全基因组关联研究（GWAS）在高加索人中已经确定了60多个T1D位点，但在亚洲了解较少。
OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (rg = 0.87), as well as subgroups of autoantibody status (rg ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10−8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10−8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10−232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10−20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10−12), 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 (P = 9.08 × 10−11) and lower fasting C-peptide levels (P = 7.19 × 10−3) in individuals newly diagnosed with T1D. CONCLUSIONS 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.
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影响因子：
30.8
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通讯作者：
Rich, Stephen S.
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
3.6
作者：
Aydintug MK;Zhang L;Wang C;Liang D;Wands JM;Michels AW;Hirsch B;Day BJ;Zhang G;Sun D;Eisenbarth GS;O'Brien RL;Born WK
通讯作者：
Born WK
影响因子：
30.8
作者：
Han B;Pouget JG;Slowikowski K;Stahl E;Lee CH;Diogo D;Hu X;Park YR;Kim E;Gregersen PK;Dahlqvist SR;Worthington J;Martin J;Eyre S;Klareskog L;Huizinga T;Chen WM;Onengut-Gumuscu S;Rich SS;Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium;Wray NR;Raychaudhuri S
通讯作者：
Raychaudhuri S
影响因子：
30.8
作者：
Fortune MD;Guo H;Burren O;Schofield E;Walker NM;Ban M;Sawcer SJ;Bowes J;Worthington J;Barton A;Eyre S;Todd JA;Wallace C
通讯作者：
Wallace C