Meng Zhu1,2,3, Kuanfeng Xu1, Yang Chen1, Yong Gu1, Mei Zhang1, Feihong Luo4, Yu Liu5, Wei Gu6, Ji Hu7, Haixia Xu8, Zhiguo Xie9,10,11, Chengjun Sun4, Yuxiu Li12, Min Sun1, Xinyu Xu1, Hsiang-Ting Hsu1, Heng Chen1, Qi Fu1, Yun Shi1, Jingjing Xu1, Li Ji1, Jin Liu1, Lingling Bian1, Jing Zhu1, Shuang Chen1, Lei Xiao1, Xin Li1, Hemin Jiang1, Min Shen1, Qianwen Huang8, Chen Fang7, Xia Li9,10,11, Gan Huang9,10,11, Jingyi Fan2, Zhu Jiang2, Yue Jiang2, Juncheng Dai2, Hongxia Ma2, Shuai Zheng1, Yun Cai1, Hao Dai1, Xuqin Zheng1, Hongwen Zhou1, Shining Ni6, Guangfu Jin2,3, Jin-Xiong She13, Liping Yu14, Constantin Polychronakos15, Zhibin Hu16,3, Zhiguang Zhou17,10,11, Jianping Weng18, Hongbing Shen16,3, Tao Yang19,20. 1. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 2. State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China. 3. Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China. 4. Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, Shanghai, China. 5. Department of Endocrinology and Metabolism, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China. 6. Department of Endocrinology, Children's Hospital of Nanjing Medical University, Nanjing, China. 7. Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Soochow University, Suzhou, China. 8. Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 9. Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China. 10. National Clinical Research Center for Metabolic Diseases, Changsha, China. 11. Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China. 12. Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. 13. Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA. 14. Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO. 15. The Endocrine Genetics Laboratory, Child Health and Human Development Program and Department of Pediatrics, McGill University Health Centre Research Institute, Montreal, Canada. 16. State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China yangt@njmu.edu.cn hbshen@njmu.edu.cn wjianp@mail.sysu.edu.cn zhouzhiguang@csu.edu.cn zhibin_hu@njmu.edu.cn. 17. Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China yangt@njmu.edu.cn hbshen@njmu.edu.cn wjianp@mail.sysu.edu.cn zhouzhiguang@csu.edu.cn zhibin_hu@njmu.edu.cn. 18. Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China yangt@njmu.edu.cn hbshen@njmu.edu.cn wjianp@mail.sysu.edu.cn zhouzhiguang@csu.edu.cn zhibin_hu@njmu.edu.cn. 19. Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China yangt@njmu.edu.cn hbshen@njmu.edu.cn wjianp@mail.sysu.edu.cn zhouzhiguang@csu.edu.cn zhibin_hu@njmu.edu.cn. 20. Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
Abstract
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 (r g = 0.87), as well as subgroups of autoantibody status (r g ≥ 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.
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 (r g = 0.87), as well as subgroups of autoantibody status (r g ≥ 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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