An association analysis of the HLA gene region in latent autoimmune diabetes in adults

Abstract

Aims/hypothesis-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.Materials and 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× 10 −16 ) and DRB1*0401_DQB1*0302 (OR=2.57, 95% CI 1.80-3.73, p=4.5×10 −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=4.2×10 −13 ). Differential susceptibility was conferred by DR4 subtypes: DRB1*0401 was predisposing (OR=1.79, 95% CI 1.35-2.38, p=2.7×10 −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=1.3×10 −8 ; and OR=6.88, 95% CI 3.54-14.68, p=1.2×10 −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/interpretation-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.

GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77

“…However, at diagnosis, the presence in these patients of circulating autoantibodies to islet cell cytoplasm (ICAs) [2], the enzyme GAD65 (GADAs) and to a lesser extent, islet-antigen 2 (IA-2As) [3], suggests an underlying autoimmune pathology. This is consistent with the known predisposition for LADA conferred by the HLA gene region [4,5]. In childhoodonset type 1 diabetes, multiple autoantibody positivity at diagnosis appears to associate with a more aggressive clinical course after onset [6].…”

“…Although GADA levels at diagnosis can help to predict the need for insulin therapy within the next 6 years [7,22] subsequent GADA measurements and fluctuations in levels are not indicators of disease progression or therapy requirement. Genetic and autoimmune markers in LADA indicate a similar aetiology to juvenile-onset diabetes [5,23,34,35] but these markers do not provide important aids to clinical management of LADA patients.…”

Relationship of Type 1 Diabetes with Human Leukocyte Antigen (HLA) Class II Antigens Except for DR3 and DR4

“…LADA has strong HLA associations apart from the same contribution of HLA in LADA and classic Type 1 diabetes (Desai et al, 2007;Hosszúfalusi et al, 2003;Stenström et al, 2003;Tuomi et al, 1999). Therefore, it is possible that the A2 type of diabetes is associated with HLA.…”

Genetic Similarities Between Latent Autoimmune Diabetes and Type 1 and Type 2 Diabetes

“…There are characteristic immune and genetic correlations with age of onset of type 1A diabetes, including lack of expression of insulin autoantibodies in adolescents and adults compared with young children and decreased percentages of the highest risk HLA genotypes. Publications on LADA analyzing the above parameters are usually consistent with older age of onset of type 1A diabetes and as indicated would not be a firm basis for distinction (16,17).…”