Genetic and immunological characteristics of Type I diabetes mellitus in an Indo-Aryan population

Abstract

Type I (insulin-dependent) diabetes results from the progressive autoimmune destruction of pancreatic beta cells [1]. The autoimmune aetiology is signified in Europid populations by a strong association with alleles of the HLA class II histocompatibility genes, particularly those carried on the DR3.DQ2 and DR4.DQ8 haplotypes [2], and the presence of circulating antibodies specific for islet antigens including glutamic acid decarboxylase (GAD), the intracellular fragment of protein tyrosine phosphatase-2 (IA-2ic) and insulin [3,4]. Diabetologia (2000) Abstract Aims/hypothesis. Our aim was to characterise the genetic and immunological features associated with Type I (insulin-dependent) diabetes mellitus in a cohort of Indo-Aryan children resident in the United Kingdom. Methods. Children with Type I diabetes (n = 53), unaffected first-degree relatives (n = 146) and unrelated healthy control children (n = 54) were typed for alleles of the HLA-DRB1, HLA-DQA1 and HLA-DQB1 genes. Islet cell antibodies and antibodies to glutamic acid decarboxylase, protein tyrosine phosphatase-2 (IA-2ic) and insulin were measured in the diabetic and control children. Results. The DRB1*03.DQA1*05.DQB1*02 haplotype was positively associated with the disease, occurring in 78 % of diabetic children compared with 22.6 % of healthy children (p c < 2.4´10 ±5 ). In simplex families, this haplotype was transmitted more frequently to the diabetic children than to their unaffected siblings (p < 1´10 ±4 ). The DRB1*04.DQA1* 03.DQB1*0302 haplotype was also transmitted preferentially to the diabetic probands (p < 0.025) but was not associated with disease in the case control study. Islet-related autoantibodies were detected in 89.6 % of diabetic patients compared with 11.8 % of control children (p < 1´10 ±6 ). Although protein tyrosine phosphatase-2 autoantibodies were detected more frequently among DRB1*04-positive diabetic patients compared with patients lacking this allele, the overall frequency of these autoantibodies was lower than observed in Europid diabetic subjects. This could reflect the absence of a disease association with DRB1*04 in the Indo-Aryan cohort. Conclusion/interpretation. Type I diabetes in our Indo-Aryan cohort is similar to the disease observed in Anglo-Europeans but has important immunogenetic differences. The low frequency of protein tyrosine phosphatase-2 autoantibodies among the Indo-Aryan diabetic children could have important implications for the design of future strategies for disease prediction in this population. [Diabetologia (2000) 43: 450±456]

Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

“…While explanation for these apparent discrepancies remain speculative at this stage, it is likely due to sample size differences, selection of study subjects, and the failure to control for potential covariates by earlier studies (1,5). The identification of DRB1*030101-DQB1*0201 and DRB1* 040101-DQB1*0302 as T1D-susceptible haplotypes and of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 as T1D-protective haplotypes was comparable to previous results with Caucasians (3,13,19,21). Of these haplotypes, regression analysis rejected DRB1*110101-DQB1*030101 as a T1D-protective haplotype, and its presence in a homozygous or heterozygous state did not impart any T1D protection aspect according to the model employed.…”

“…Thus, it appears that DQB1*0201 did not play a significant role in T1D pathogenesis and that the disease protection or susceptibility may be explained the presence of DQB1*0201 haplotypes with protective or susceptible DRB1 alleles, respectively, as was also suggested elsewhere (10). DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were strongly associated with, while DRB1*070101-DQB1* 0201 was protective of T1D, further supporting the notion that DRB1*030101-DQB1*0201 on its own is a major T1D susceptibility haplotype among Caucasians (3,13,19). Our findings were reminiscent of earlier studies of Tunisians, which showed that DR3 and DR4 (1,5) and DRB1*03-DQB1*0201 and DRB1*04-DQB1*0302 haplotypes (1) were strongly associated with T1D.…”

“…The DRB1* 030101-DQB1*0201 haplotype fitted a recessive model, since it confers strong T1D susceptibility when present in a homozygous state (Pc ϭ 2.5 ϫ 10 Ϫ4 ; OR ϭ 43.79), rather than in a heterozygous state (Pc ϭ 0.089; OR ϭ 5.19). The high T1D susceptibility conferred by both DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 haplotypes was reminiscent of previous studies of Caucasians (3,13,16,19), but not nonCaucasians (12), supporting the notion of Caucasian T1D susceptibility haplotypes. DQB1*0302 was strongly associated with, while DQB1* 030101 was largely protective of T1D.…”

Latent Autoimmune Diabetes in Adults (LADA): The Prevalent Form of Adult-Onset Autoimmune Diabetes in a Region of India

“…The expected difference in LADA prevalence using only GADA or GADA along with other diabetes autoantibody would not be significant [15]. In the past, low frequency of IA-2 autoantibody has been reported among adults of North Indian origin and Indo-Aryan children with DM1 [33,34].…”

“…There are no prevalence data available for adult-onset (> 30 years) DM-1A in North Indians but earlier studies have shown the prevalence of DM1-A to be lower among children and adolescents in North Indian populations than in Caucasians [34,36].…”