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

Meng Zhu^{1

2

3}, Kuanfeng Xu¹, Yang Chen¹, Yong Gu¹, Mei Zhang¹, Feihong Luo⁴, Yu Liu⁵, Wei Gu⁶, Ji Hu⁷, Haixia Xu⁸, Zhiguo Xie^{9

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 Li^{9

10

11}, Gan Huang^{9

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 Jin^{2

3}, Jin-Xiong She¹³, Liping Yu¹⁴, Constantin Polychronakos¹⁵, Zhibin Hu^{16

3}, Zhiguang Zhou^{17

10

11}, Jianping Weng¹⁸, Hongbing Shen^{16

3}, Tao Yang^{19

20}

Affiliations

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.

PMID: 31152121
DOI: 10.2337/dc18-2023

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

Meng Zhu et al. Diabetes Care. 2019 Aug.

. 2019 Aug;42(8):1414-1421.

doi: 10.2337/dc18-2023. Epub 2019 May 31.

Authors

Affiliations

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.

PMID: 31152121
DOI: 10.2337/dc18-2023

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.

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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

Affiliations

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

Authors

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Abstract

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Medical

Research Materials