Geographical Variation in Risk HLA-DQB1 Genotypes for Type 1 Diabetes and Signs of β-Cell Autoimmunity in a High-Incidence Country

Abstract

OBJECTIVE -To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of ␤-cell autoimmunity among three geographical regions in Finland.RESEARCH DESIGN AND METHODS -The series comprised 4,642 children with increased HLA-DQB1-defined genetic risk of type 1 diabetes from the Diabetes Prediction and Prevention (DIPP) study: 1,793 (38.6%) born in Turku, 1,646 (35.5%) in Oulu, and 1,203 (25.9%) in Tampere. These children were examined frequently for the emergence of signs of ␤-cell autoimmunity, for the primary screening of which islet cell antibodies (ICA) were used. If the child developed ICA, all samples were also analyzed for insulin autoantibodies (IAA), GAD65 antibodies (GADA), and antibodies to the IA-2 molecule (IA-2A).RESULTS -The high-and moderate-risk genotypes were unevenly distributed among the three areas (P Ͻ 0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) than in the Turku (28.4%; P Ͻ 0.001) or Tampere regions (27.2%; P Ͻ 0.001). This genotype was associated with an increased frequency of ICA seroconversion relative to the moderate risk genotypes (hazard ratio 1.89, 95% CI 1.36 -2.62). Seroconversions to ICA positivity occurred less commonly in Tampere than in Turku (0.47, 0.28 -0.75), whereas the seroconversion rate in Oulu did not differ from that in Turku (0.72, 0.51-1.03). The Tampere-Turku difference persisted after adjustment for risk genotypes, sex, and time of birth (before January 1998 versus later). Seroconversion for at least one additional autoantibody was also less frequent in Tampere than in Turku (0.39,.CONCLUSIONS -These data show that in Finland, the country with the highest incidence of type 1 diabetes in the world, both the frequency of the high-risk HLA-DQB1 genotype and the risk of seroconversion to autoantibody positivity show geographical variation. The difference in seroconversion rate could not be explained by the difference in HLA-DQB1-defined disease susceptibility, implying that the impact of environmental triggers of diabetes-associated autoimmunity may differ between the three regions studied. Diabetes Care 27:676 -681, 2004T he epidemiological map of type 1 diabetes that has been drawn over the last few decades shows marked differences in the incidence of the disease among countries and various racial groups (1,2). The reasons behind these differences have remained poorly defined, but both genetic and environmental factors may contribute to them. Type 1 diabetes is a polygenic disorder, but it has been estimated that the genes of the HLA complex explain 30 -60% of its familial clustering (3). The main genes contributing to disease susceptibility are located in the HLA-DQ locus on the short arm of chromosome 6, 6p21 (4), and alleles at this locus also provide resistance to diabetes. There are some differences within Europe in the distribution of the HLA risk alleles among patients affected by type 1 diabetes. The proportion of DQB1*02-positive subjects is higher among patients from southern Europe, wh...

Spatiotemporal Trends and Age-Period-Cohort Modeling of the Incidence of Type 1 Diabetes Among Children Aged <15 Years in Norway 1973–1982 and 1989–2003

“…It is difficult to imagine that genetic factors can explain the increasing incidence of type 1 diabetes over time; although the Norwegian and other Nordic populations are commonly believed to be relatively homogeneous, we cannot exclude the possibility that some of the spatial variation is due to genetic factors. Previous studies have shown that the high-risk HLA genotype could explain some of the variations between European countries (25) and even between three areas in Finland (26). We have, however, previously reported that the prevalence of the high-risk HLA genotype in the general population in Vest-Agder county (27) is very similar to that identified in Norway as a whole (28).…”

Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes

“…To achieve this, newborn infants (n=373), who had the highest risk HLA genotype (DR3)-DQA1*05-DQB1*02/DRB1*0401-DQB1*0302 (from n=546; HLA-DR3/DR4 [25]), were matched with unaffected newborn infants with the identical HLA genotype, from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study (n = 373) [26]. A subgroup of children was also used for circulating soluble RAGE analyses.…”

Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study

“…The assays of islet-cell antibodies (ICA), insulin autoantibodies (IAA), anti-glutamic acid decarboxylase antibodies (GADA) and anti-insulinoma-associated antigen-2 antibodies (IA-2A) are described in detail in a recent paper by Kukko et al [12]. The disease sensitivity of the ICA assay was 100% and the specificity 98% in the Fourth Immunology and Diabetes Workshop for the Standardisation of Cytoplasmic ICA [13].…”