title: Attenuated humoral responses in HLA-A*24-positive individuals at risk of type 1 diabetes.
abstract: OBJECTIVE
  The rate of progression from islet autoimmunity to clinical type 1 diabetes depends on the rate of beta cell destruction. The HLA-A*24 gene is associated with early diabetes onset, but previous studies have shown attenuated humoral responses to islet antigens in individuals with both recent and long-standing type 1 diabetes carrying HLA-A*24. We aimed to establish whether HLA-A*24 is also associated with attenuated humoral responses in individuals at high risk of type 1 diabetes.
  
  
  METHODS
  We established HLA-A*24, DQ and rs9258750 (an HLA-A*24 tagged single-nucleotide polymorphism) genotype, as well as GAD, zinc transporter 8 (ZnT8), insulin, islet antigen-2 (IA-2), and IA-2β autoantibody status in 373 islet cell antibody-positive first-degree relatives participating in the European Nicotinamide Diabetes Intervention Trial.
  
  
  RESULTS
  Univariate regression analyses showed that humoral responses to GAD, ZnT8 and insulin were less common in relatives carrying HLA-A*24. The prevalence of GAD and ZnT8 autoantibodies remained negatively associated with HLA-A*24 and rs9258750 after adjusting for age, sex, proband relationship and HLA class II genotype.
  
  
  CONCLUSIONS
  HLA-A*24 is associated with attenuated humoral responses in individuals at high risk of type 1 diabetes, and this may reflect a distinct phenotype of rapid beta cell loss.
authors.affiliation: Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Jody
authors.initials: J
authors.lastname: Ye
authors.affiliation: Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Long
authors.affiliation: Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Pearson
authors.affiliation: Research Design Service-South West, Education Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Taylor
authors.affiliation: Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.affiliation: Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK.
authors.forename: Alistair J K
authors.initials: AJ
authors.lastname: Williams
authors.affiliation: Diabetes and Metabolism, School of Clinical Sciences, University of Bristol, Level 2 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK. k.m.gillespie@bristol.ac.uk.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillespie
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D015234:HLA-A Antigens
keywords: Autoantibodies; HLA-A*24; Type 1 diabetes