HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion

Diabetologia. 2011 Jul;54(7):1684-92. doi: 10.1007/s00125-011-2122-8. Epub 2011 Apr 12.


Aims/hypothesis: We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona.

Methods: Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits.

Results: The A allele at rs9268852, which tags HLA-DRB1 02(1602), was associated both with higher HLA-DRB1 mRNA expression (n = 133, p = 4.27 × 10(-14)) and decreased risk of type 2 diabetes (n = 3,265, OR 0.723, p = 0.002). Among persons with normal glucose tolerance (n = 266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p = 0.005), higher mean 30 min insulin concentration during an oral glucose tolerance test (p = 0.017) and higher body fat percentage (p = 0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity.

Conclusions/interpretation: HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.

Publication types

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

MeSH terms

  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Female
  • Genetic Predisposition to Disease
  • HLA-DR Antigens / genetics*
  • HLA-DR Antigens / metabolism
  • HLA-DR alpha-Chains
  • HLA-DRB1 Chains
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Male
  • Muscle, Skeletal / metabolism
  • Polymorphism, Single Nucleotide / genetics


  • HLA-DR Antigens
  • HLA-DR alpha-Chains
  • HLA-DRB1 Chains
  • Insulin