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

Diabetes Care. 2019 Aug;42(8):1414-1421. doi: 10.2337/dc18-2023. Epub 2019 May 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors*
  • Antigens, CD / genetics*
  • Asian People / genetics
  • Autoantibodies / blood
  • Butyrophilins / genetics*
  • C-Peptide / blood
  • Child
  • China
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Fasting / blood
  • Female
  • GATA3 Transcription Factor / genetics*
  • Genetic Loci / genetics*
  • Genome-Wide Association Study
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Male
  • Odds Ratio
  • Oxidoreductases Acting on Sulfur Group Donors / genetics
  • Risk Factors

Substances

  • Antigens, CD
  • Autoantibodies
  • BTN3A1 protein, human
  • Butyrophilins
  • C-Peptide
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Histocompatibility Antigens Class I
  • Oxidoreductases Acting on Sulfur Group Donors
  • SUOX protein, human