title: HLA-DRB1 reduces the risk of type 2 diabetes mellitus by increased insulin secretion.
abstract: OBJECTIVE
  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
  HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1550 East Indian School Road, Phoenix, AZ 85014, USA. williamsr@mail.nih.gov
authors.forename: R C
authors.initials: RC
authors.lastname: Williams
authors.forename: Y L
authors.initials: YL
authors.lastname: Muller
authors.forename: R L
authors.initials: RL
authors.lastname: Hanson
authors.forename: W C
authors.initials: WC
authors.lastname: Knowler
authors.forename: C C
authors.initials: CC
authors.lastname: Mason
authors.forename: L
authors.initials: L
authors.lastname: Bian
authors.forename: V
authors.initials: V
authors.lastname: Ossowski
authors.forename: K
authors.initials: K
authors.lastname: Wiedrich
authors.forename: Y F
authors.initials: YF
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Marcovina
authors.forename: J
authors.initials: J
authors.lastname: Hahnke
authors.forename: R G
authors.initials: RG
authors.lastname: Nelson
authors.forename: L J
authors.initials: LJ
authors.lastname: Baier
authors.forename: C
authors.initials: C
authors.lastname: Bogardus
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D007328:Insulin