title: An association analysis of the HLA gene region in latent autoimmune diabetes in adults.
abstract: OBJECTIVE
  Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis.
  
  
  METHODS
  Patients with LADA (n = 387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (n = 327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR.
  
  
  RESULTS
  As in type 1 diabetes mellitus, DRB1 0301_DQB1 0201 (odds ratio [OR] = 3.08, 95% CI 2.32-4.12, p = 1.2 x 10(-16)) and DRB1 0401_DQB1 0302 (OR = 2.57, 95% CI 1.80-3.73, p = 4.5 x 10(-8)) were the main susceptibility haplotypes in LADA, and DRB1 1501_DQB1 0602 was protective (OR = 0.21, 95% CI 0.13-0.34, p = 4.2 x 10(-13)). Differential susceptibility was conferred by DR4 subtypes: DRB1 0401 was predisposing (OR = 1.79, 95% CI 1.35-2.38, p = 2.7 x 10(-5)) whereas DRB1 0403 was protective (OR = 0.37, 95% CI 0.13-0.97, p = 0.033). The highest-risk genotypes were DRB1 0301/DRB1 0401 and DQB1 0201/DQB1 0302 (OR = 5.14, 95% CI 2.68-10.69, p = 1.3 x 10(-8); and OR = 6.88, 95% CI 3.54-14.68, p = 1.2 x 10(-11), respectively). These genotypes and those containing DRB1 0401 and DQB1 0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1 1501 and DQB1 0602 associated with an older age at diagnosis.
  
  
  CONCLUSIONS
  Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes.
authors.affiliation: Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Headington, Oxford, OX3 7LJ, UK.
authors.forename: M
authors.initials: M
authors.lastname: Desai
authors.forename: E
authors.initials: E
authors.lastname: Zeggini
authors.forename: V A
authors.initials: VA
authors.lastname: Horton
authors.forename: K R
authors.initials: KR
authors.lastname: Owen
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: J C
authors.initials: JC
authors.lastname: Levy
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.forename: K M
authors.initials: KM
authors.lastname: Gillespie
authors.forename: P J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: G A
authors.initials: GA
authors.lastname: Hitman
authors.forename: R R
authors.initials: RR
authors.lastname: Holman
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: A
authors.initials: A
authors.lastname: Clark
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006113:United Kingdom
chemical_list: D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen