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

Author:

Zhu Meng123,Xu Kuanfeng1,Chen Yang1,Gu Yong1,Zhang Mei1ORCID,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 Liping14ORCID,Polychronakos Constantin15ORCID,Hu Zhibin23,Zhou Zhiguang91011ORCID,Weng Jianping8ORCID,Shen Hongbing23,Yang Tao116ORCID

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

Reference34 articles.

1. Type 1 diabetes mellitus;Katsarou;Nat Rev Dis Primers,2017

2. Genetic risk factors for type 1 diabetes;Pociot;Lancet,2016

3. Environmental risk factors for type 1 diabetes;Rewers;Lancet,2016

4. HL-A antigens and diabetes mellitus;Nerup;Lancet,1974

5. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families;Noble;Am J Hum Genet,1996

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3