期刊
DIABETES CARE
卷 42, 期 8, 页码 1414-1421出版社
AMER DIABETES ASSOC
DOI: 10.2337/dc18-2023
关键词
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资金
- National Key Project of Research and Development Plan [2016YFC1000204, 2016YFC1305302, 2016YFC1305000, 2016YFC1305001]
- National Key Technologies R&D Program of China [2015BAI12B13]
- Innovation-Driven Program of Central South University [2015CX009]
- Cheung Kong Scholars Program of China
- National Natural Science Foundation of China [81390543, 81270897, 81670715, 81670756, 81370939, 81300668, 81400808, 81400813, 81803306, 81830023, 81530026, 81530025]
- Jiangsu Specially Appointed Professor project
- Science and Technology Innovation Team of Jiangsu Province Qinglan Project
- Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine)
- Top-Notch Academic Programs Project of Jiangsu Higher Education Institutions [PPZY2015A067]
- Jiangsu Province Key Science and Technology Development Project [BE2017753]
- Jiangsu Province Science Foundation for Youth [BK20171082, BK20180675]
- Three Big Constructions funds of Sun Yat-sen University [8200031133402]
- Science and Technology Commission of Shanghai Municipality [STCSM 15411961700]
- Beijing Science and Technology project [Z151100003915077]
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 x 10(-8)) and rs3802604 in GATA3 (OR 1.24, P = 2.06 x 10(-8)), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 x 10(-232)) and rs705699 in SUOX (OR 1.46, P = 7.48 x 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 x 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 x 10(-11)) and lower fasting C-peptide levels (P = 7.19 x 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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