Geographical Variation in Risk HLA- DQB1 Genotypes for Type 1 Diabetes and Signs of ß-Cell Autoimmunity in a High-Incidence
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Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE Geographical Variation in Risk HLA- DQB1 Genotypes for Type 1 Diabetes and Signs of -Cell Autoimmunity in a High-Incidence Country 1,2 1,6 MARIKA KUKKO, MD SARI KORHONEN, MD he epidemiological map of type 1 di- 1,2,3,4 1,7 SUVI M. VIRTANEN, MD, MSC, PHD JORMA ILONEN, MD, PHD abetes that has been drawn over the 1,2 1,5 ANNA TOIVONEN, MD OLLI SIMEL, MD, PHD 1,5 1,2,8 last few decades shows marked dif- ATU IMELL MD IKAEL NIP MD, PHD T S S , M K , ferences in the incidence of the disease among countries and various racial groups (1,2). The reasons behind these differences have remained poorly de- fined, but both genetic and environmen- 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. tal factors may contribute to them. Type 1 diabetes is a polygenic disorder, but it has RESEARCH DESIGN AND METHODS — The series comprised 4,642 children with been estimated that the genes of the HLA increased HLA-DQB1–defined genetic risk of type 1 diabetes from the Diabetes Prediction and complex explain 30–60% of its familial Prevention (DIPP) study: 1,793 (38.6%) born in Turku, 1,646 (35.5%) in Oulu, and 1,203 clustering (3). The main genes contribut- (25.9%) in Tampere. These children were examined frequently for the emergence of signs of ing to disease susceptibility are located in -cell autoimmunity, for the primary screening of which islet cell antibodies (ICA) were used. If the HLA-DQ locus on the short arm of the child developed ICA, all samples were also analyzed for insulin autoantibodies (IAA), GAD65 chromosome 6, 6p21 (4), and alleles at antibodies (GADA), and antibodies to the IA-2 molecule (IA-2A). this locus also provide resistance to dia- RESULTS — The high- and moderate-risk genotypes were unevenly distributed among the betes. There are some differences within three areas (P Ͻ 0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) Europe in the distribution of the HLA risk than in the Turku (28.4%; P Ͻ 0.001) or Tampere regions (27.2%; P Ͻ 0.001). This genotype alleles among patients affected by type 1 was associated with an increased frequency of ICA seroconversion relative to the moderate risk diabetes. The proportion of DQB1*02- genotypes (hazard ratio 1.89, 95% CI 1.36–2.62). Seroconversions to ICA positivity occurred positive subjects is higher among patients less commonly in Tampere than in Turku (0.47, 0.28–0.75), whereas the seroconversion rate in from southern Europe, whereas the Oulu did not differ from that in Turku (0.72, 0.51–1.03). The Tampere-Turku difference DQB1*0302 haplotype is more common persisted after adjustment for risk genotypes, sex, and time of birth (before January 1998 versus in northern Europe (5). We have previ- later). Seroconversion for at least one additional autoantibody was also less frequent in Tampere ously shown in the Diabetes Prediction than in Turku (0.39, 0.16–0.82). and Prevention (DIPP) study that hetero- CONCLUSIONS — These data show that in Finland, the country with the highest incidence geneity exists within Finland in the prev- of type 1 diabetes in the world, both the frequency of the high-risk HLA-DQB1 genotype and the alence of HLA-DQ genotypes and alleles risk of seroconversion to autoantibody positivity show geographical variation. The difference in associated with the risk of type 1 diabetes. seroconversion rate could not be explained by the difference in HLA-DQB1–defined disease That study was performed in two regions susceptibility, implying that the impact of environmental triggers of diabetes-associated auto- located in the southwest (Turku) and immunity may differ between the three regions studied. northern (Oulu) parts of the country; the HLA-DQB1*02 risk allele was more com- Diabetes Care 27:676–681, 2004 mon in the Turku region and ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● DQB1*0302 was more common in the From the 1Juvenile Diabetes Research Foundation Center for the Prevention of Type 1 Diabetes in Finland, Oulu region (6). 2 Tampere, Finland; the Medical School, University of Tampere, and Department of Pediatrics, Tampere Reports on variations in the incidence University Hospital, Tampere, Finland; the 3Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland; the 4Tampere School of Public Health, University of Tampere, rate of type 1 diabetes within specific Tampere, Finland; the 5Department of Pediatrics, University of Turku, Turku, Finland; the 6Department of countries are less common than compar- Pediatrics, University of Oulu, Oulu, Finland; the 7Department of Virology, University of Turku, Turku, isons among countries, but clear varia- Finland; and the 8Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland. tions have been observed within the 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@hus.fi. Nordic countries (Finland, Norway, and Received for publication 27 March 2003 and accepted in revised form 13 October 2003. Sweden) in the 1970s (7–9), in England Abbreviations: DASP, Diabetes Autoantibody Standardization Program; DIPP, Diabetes Prediction and in the 1980s (10), and more recently in Prevention; GADA, GAD65 antibody; IAA, insulin autoantibody; ICA, islet cell antibody; IA-2A, antibody to Germany (11). In Europe, this within- the IA-2 molecule. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion country variation is most conspicuous in factors for many substances. Italy, with the incidence close to four © 2004 by the American Diabetes Association. times higher in Sardinia than on the main- 676 DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 Kukko and Associates informed consent to the genetic screen- ing. Families in which neither of the par- ents was of Caucasian origin (Ͼ99% of the Finnish population are Caucasian), in which the parents had difficulty under- standing Finnish, Swedish, or English, or in which the newborn infant had a severe congenital disease were excluded from the study. During the time period be- tween November 1994 and November 2000, 47,605 infants were screened for HLA-DQB1–conferred genetic risk. Fam- ilies with an infant carrying increased HLA-conferred susceptibility to type 1 di- abetes (n ϭ 5,978; 12.6% of all screened) were invited for observation and immu- nological surveillance for the emergence of diabetes-associated autoantibodies and development of type 1 diabetes. The present series comprised 4,642 such chil- dren (77.7% of those invited) from the three regions of Finland, of whom 52.7% (2,447) were boys. Serum samples for the immunologi- cal surveillance were taken at the ages of 3, 6, 12, 18, 24, and 36 months, and the present analysis is based on samples taken before the end of March 2001. The proto- col was approved by the ethical commit- tees of the three participating hospitals, Figure 1—Location of the three university hospital regions cov- and informed consent was obtained from ered by the study and the distances the parents or guardians of the children. between the three cities. Genetic screening HLA-DQB1 typing was performed by a land (12,13). In China, where the inci- bodies to the IA-2 molecule (IA-2As), previously described method based on dence rate is one of the lowest reported, a markedly increase the risk of progression time-resolved fluorescence (19). Five se- 12-fold geographical variation has been to type 1 diabetes in subjects carrying quence-specific oligonucleotide probes observed (14). Regional variation was also HLA-DQ susceptibility alleles, we de- were used to identify the following DQB1 reported in Finland during the late 1980s cided to assess whether the prevalence of alleles known to be significantly associ- (15), with persistently high-risk areas lo- the HLA-DQB1 risk genotypes differs ated with either susceptibility to or pro- cated in central Finland from 1987 to among the three regions of Finland (Tam- tection against type 1 diabetes in the 1996, although the geographical pattern pere, Turku, Oulu) covered by the DIPP Finnish population: DQB1*0302, changed with time (16). It has also been study and whether ICA alone or in com- DQB1*02, DQB1*0602, DQB1*0603, suggested that autoimmunity in first- bination with other diabetes-associated and DQB1*0301. The subjects were clas- degree relatives of patients with type 1 autoantibodies emerge at different rates in sified into four risk groups based on their diabetes occurs with similar frequencies these three regions (Fig. 1). HLA-DQB1 genotype using a previously in different European countries despite described simplified classification: high the wide variation in the incidence of the RESEARCH DESIGN AND risk (DQB1*02/0302), moderate risk clinical disease (17). However, when the METHODS — Screening of HLA-DQ (DQB1*0302/x; where x indicates *0302 prevalence of -cell autoimmunity and risk alleles in newborn infants was initi- or a nondefined allele), low risk the incidence of type 1 diabetes in the ated at the Turku University Hospital in (DQB1*0301/0302, DQB1*02/0301, background population were compared November 1994, at the Oulu University DQB1*02/x, DQB1*0302/0602; where x in eight European countries, a relatively Hospital in September 1995, and at the indicates *02 or a nondefined allele), and close correlation was found between the Tampere University Hospital in October decreased risk (protection) (DQB1*x/x, two parameters (18). 1997.