Elsevier

Human Immunology

Volume 42, Issue 2, February 1995, Pages 116-122
Human Immunology

HLA antigens and age at diagnosis of insulin-dependent diabetes mellitus

https://doi.org/10.1016/0198-8859(94)00075-2Get rights and content

Abstract

IDDM results from the immune-mediated destruction of pancreatic islet β cells. Clinicopathologic heterogeneity in IDDM is reflected in part by the wide age range over which the onset of clinical symptoms can occur, after months to years of subclinical “insulitis.” Because MHC genes play a critical role in immune function we studied their possible contribution to IDDM heterogeneity by analyzing HLA profiles of 194 IDDM patients in relation to their age at diagnosis. Restriction of HLA-DR heterogeneity was observed in patients diagnosed before age 21 years. Frequencies of DR3 and DR34 were highest in the ⩽6-year-old age group and thereafter declined with increasing age at diagnosis. In contrast, the frequency of DR4 remained increased up to age 30 years at diagnosis. DR7, normally considered to be a neutral allele, was like DR2 and DR 5, significantly decreased in patients diagnosed before age 21 years. The A30-B18-DR3 haplotype was significantly increased in the ⩽6-year-old age group, A1-B8-DR3 was increased in the ⩾31-year-old group. B62-DR4 was increased only in the > 12-year-old age group. In DR4 patients the frequency of DQ8 was increased across all age groups. A sex difference was observed in those diagnosed at ⩽ 12 years of age, with an excess of females in the DR3+/DR4 group and males in the DR3DR4+ group. An association of DPB 1 with IDDM was revealed by an increased frequency overall of DPB 10301 and/or DPB 10401, being more pronounced in patients diagnosed at >20 years of age. Thus, early age at diagnosis of IDDM is associated with a restricted number of DR and DQ haplotypes. Older age at diagnosis is associated with an increase in heterogeneity of DRB 1 and a decrease in heterogeneity of DPB 1. These findings imply that a limited range of HLA class II peptide complexes determine the age at which IDDM presents clinically, possibly by influencing the nature of β-cell autoimmunity and the rate of progression of β-cell destruction.

References (33)

  • G Schernthaner et al.

    Juvenile diabetes mellitus: HLA antigen frequencies dependent on the age of onset of the disease

    J Immunogenet

    (1976)
  • A Mustonen et al.

    An analysis of epidemiological data in HLA typed diabetic children

    Diabetologia

    (1985)
  • J Ludvigsson et al.

    DR3 is associated with a more slowly progressive form of type 1 (insulin-dependent) diabetes

    Diabetologia

    (1986)
  • A Svejgaard et al.

    HLA associations in insulin-dependent diabetes: search for heterogeneity in different groups of patients from a homogeneous population

    Tissue Antigens

    (1986)
  • I Deschamps et al.

    Two distinct HLA-DR3 haplotypes are associated with age-related heterogeneity in type 1 (insulin-dependent) diabetes

    Diabetologia

    (1988)
  • S Caillat-Zucman et al.

    Age-dependent HLA genetic heterogeneity of type 1 insulindependent diabetes mellitus

    J Clin Invest

    (1992)
  • Cited by (76)

    • Prevention of Autoimmune Disease: The Type 1 Diabetes Paradigm

      2013, The Autoimmune Diseases: Fifth Edition
    • Tumor necrosis factor-associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes

      2012, Human Immunology
      Citation Excerpt :

      It is interesting to note that the B8–DR3 haplotypes alone were associated with late age of onset of T1D (10–20 years, 40.3%, and >20 years, 35.3%, compared with <10 years, 18.9%) in the Indian population. A similar study in Caucasians reported that the frequency of the HLA-A1–B8–DR3 haplotypes was increased in patients ≥31 years of age at diagnosis, whereas A30–B18–DR3 occurred primarily in the ≤6-year age group and B62–DR4 in those with disease at onset at ≥12 years [68]. Because the B8–DR3 haplotypes differ at several loci between Caucasians and North Indians, including polymorphisms TNF −308 and TNFa genes, the delayed onset of the disease cannot be attributed only to the TNF block of the B8–DR3 haplotypes and might be influenced by other factors.

    • Diabetes related autoimmunity in gestational diabetes mellitus: Is it important?

      2009, Nutrition, Metabolism and Cardiovascular Diseases
      Citation Excerpt :

      HLA typing is useful in assessing the risk of type 1 diabetes in relatives of type 1 diabetic patients. The DRB1*03,04DQBI*;0201,0302 (DR3,4-DQ2,8) sequence coincides with relatives having a more than 20-fold risk of developing diabetes and is associated with an earlier age at diagnosis [11]. The other characteristic sequences, such as DRB1*04,04; DQB1*0302,0302(DR4,4-DQ8,8), DRB1*03,03; DQB1*0302,Y(DR3,3-DQ8,Y),DRB1*04,03; DQB1*0302,Y(DR4,X-DQ8,Y) and DRB1*03,X, correlate with a lower risk of developing type 1 diabetes.

    • Searching for Additional Disease Loci in a Genomic Region

      2008, Advances in Genetics
      Citation Excerpt :

      For an additive (dominant) model, most patients are expected to be heterozygous rather than homozygous for the associated marker allele. Also, additive expectations continue to hold if we additionally allow for sporadic cases when the marker locus is itself the disease causative agent, for example, HLA‐B27 and ankylosing spondilitis (Thomson, 1983). Expectations for multiple alleles are easily obtained allowing tests of mode of inheritance (Thomson, 1993, 1995a); however, the simple method of moments estimate for the additive model can give problems with multiple alleles if the mode of inheritance is not close to additive.

    View all citing articles on Scopus
    View full text