Genetic association of zinc transporter 8 (ZnT8) autoantibodies in type 1 diabetes cases

Diabetologia. 2012 Jul;55(7):1978-84. doi: 10.1007/s00125-012-2540-2. Epub 2012 Apr 12.

Abstract

Aims/hypothesis: Autoantibodies to zinc transporter 8 (ZnT8A) are associated with risk of type 1 diabetes. Apart from the SLC30A8 gene itself, little is known about the genetic basis of ZnT8A. We hypothesise that other loci in addition to SLC30A8 are associated with ZnT8A.

Methods: The levels of ZnT8A were measured in 2,239 British type 1 diabetic individuals diagnosed before age 17 years, with a median duration of diabetes of 4 years. Cases were tested at over 775,000 loci genome wide (including 53 type 1 diabetes associated regions) for association with positivity for ZnT8A. ZnT8A were also measured in an independent dataset of 855 family members with type 1 diabetes.

Results: Only FCRL3 on chromosome 1q23.1 and the HLA class I region were associated with positivity for ZnT8A. rs7522061T>C was the most associated single nucleotide polymorphism (SNP) in the FCRL3 region (p = 1.13 × 10(-16)). The association was confirmed in the family dataset (p ≤ 9.20 × 10(-4)). rs9258750A>G was the most associated variant in the HLA region (p = 2.06 × 10(-9) and p = 0.0014 in family cases). The presence of ZnT8A was not associated with HLA-DRB1, HLA-DQB1, HLA-A, HLA-B or HLA-C (p > 0.05). Unexpectedly, the two loci associated with the presence of ZnT8A did not alter risk of having type 1 diabetes, and the 53 type 1 diabetes risk loci did not influence positivity for ZnT8A, despite them being disease specific.

Conclusions/interpretation: ZnT8A are not primary pathogenic factors in type 1 diabetes. Nevertheless, ZnT8A testing in combination with other autoantibodies facilitates disease prediction, despite the biomarker not being under the same genetic control as the disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / genetics*
  • Cation Transport Proteins / genetics*
  • Cation Transport Proteins / immunology
  • Child
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Insulin Antibodies / genetics*
  • Insulin Antibodies / immunology
  • Male
  • Polymorphism, Single Nucleotide*
  • Zinc Transporter 8

Substances

  • Autoantibodies
  • Cation Transport Proteins
  • Insulin Antibodies
  • SLC30A8 protein, human
  • Zinc Transporter 8