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

• Published in: Diabetes care Vol. 42; no. 8; pp. 1414 - 1421
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2019
• 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; China
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc18-2023

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.