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-Reference-Cited by-同舟云学术

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:2019-05-31 Issue:8 Volume:42 Page:1414-1421
ISSN:0149-5992
Container-title:Diabetes Care
language:en
Short-container-title:

Author:

Zhu Meng¹²³,Xu Kuanfeng¹,Chen Yang¹,Gu Yong¹,Zhang Mei¹^ORCID,Luo Feihong⁴,Liu Yu⁵,Gu Wei⁶,Hu Ji⁷,Xu Haixia⁸,Xie Zhiguo⁹¹⁰¹¹,Sun Chengjun⁴,Li Yuxiu¹²,Sun Min¹,Xu Xinyu¹,Hsu Hsiang-Ting¹,Chen Heng¹,Fu Qi¹,Shi Yun¹,Xu Jingjing¹,Ji Li¹,Liu Jin¹,Bian Lingling¹,Zhu Jing¹,Chen Shuang¹,Xiao Lei¹,Li Xin¹,Jiang Hemin¹,Shen Min¹,Huang Qianwen⁸,Fang Chen⁷,Li Xia⁹¹⁰¹¹,Huang Gan⁹¹⁰¹¹,Fan Jingyi²,Jiang Zhu²,Jiang Yue²,Dai Juncheng²,Ma Hongxia²,Zheng Shuai¹,Cai Yun¹,Dai Hao¹,Zheng Xuqin¹,Zhou Hongwen¹,Ni Shining⁶,Jin Guangfu²³,She Jin-Xiong¹³,Yu Liping¹⁴^ORCID,Polychronakos Constantin¹⁵^ORCID,Hu Zhibin²³,Zhou Zhiguang⁹¹⁰¹¹^ORCID,Weng Jianping⁸^ORCID,Shen Hongbing²³,Yang Tao¹¹⁶^ORCID

Affiliation:

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. 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 (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.

Publisher

American Diabetes Association

Subject

Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine

Link

https://diabetesjournals.org/care/article-pdf/42/8/1414/529313/dc182023.pdf

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