Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country.
OBJECTIVE
To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of beta-cell autoimmunity among three geographical regions in Finland.


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 beta-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.
Kukko
Marika
M
Juvenile Diabetes Research Foundation Center for the Prevention of Type 1 Diabetes in Finland, Tampere, Finland.
Virtanen
Suvi M
SM
Toivonen
Anna
A
Simell
Satu
S
Korhonen
Sari
S
Ilonen
Jorma
J
Simel
Olli
O
Knip
Mikael
M
D001323:Autoantibodies / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D005843:Geography; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006801:Humans; D015994:Incidence; D007223:Infant; D007515:Islets of Langerhans / Q000276:immunology*; D016016:Proportional Hazards Models; D018570:Risk Assessment; D013997:Time Factors
D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C024211:islet cell antibody