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

¹ Juvenile Diabetes Research Foundation Center for the Prevention of Type 1 Diabetes in Finland, Tampere, Finland
² Medical School, University of Tampere, and Department of Pediatrics, Tampere University Hospital, Tampere, Finland
³ Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
⁴ Tampere School of Public Health, University of Tampere, Tampere, Finland
⁵ Department of Pediatrics, University of Turku, Turku, Finland
⁶ Department of Pediatrics, University of Oulu, Oulu, Finland
⁷ Department of Virology, University of Turku, Turku, Finland
⁸ Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland

Address correspondence and reprint requests to Mikael Knip, MD, Hospital for Children and Adolescents University of Helsinki, P.O. Box 281, FIN-00029 HUCH, Helsinki, Finland. E-mail: mikael.knip{at}hus.fi

OBJECTIVE—To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of ß-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 ß-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 < 0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) than in the Turku (28.4%; P < 0.001) or Tampere regions (27.2%; P < 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, 0.16–0.82).

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.

Abbreviations: DASP, Diabetes Autoantibody Standardization Program • DIPP, Diabetes Prediction and Prevention • GADA, GAD65 antibody • IAA, insulin autoantibody • ICA, islet cell antibody • IA-2A, antibody to the IA-2 molecule

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