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Currently more than 50 type 1 diabetes (T1D) loci outside the human leukocyte antigen (HLA)-region have been established in large European and/or North American populations. Our aim was to attempt to replicate these findings in the less heterogenic Finnish population and to explore evidence for genetic heterogeneity. We analyzed 1761 Finnish T1D trio families for association in 31 T1D loci (25 confirmed and 6 have inconsistent prior evidence). Families were categorized into nine different subgroups according to potential features that reflect underlying genetic heterogeneity in patients (age at diagnosis, sex and HLA genotypes). Seventeen confirmed loci and one nonconfirmed locus (1p31.1) presented significant evidence for association in the full data set. Magnitude and direction of effect was consistent with prior evidence. The strongest effects were seen at the insulin gene, PTPN22 and IL2RA regions. Tentative evidence of odds ratio (OR) heterogeneity within subgroups was seen in eight loci. Our findings were well in line with those reported in the latest meta-analyses using large admixed Caucasian populations, which concurs with the notion that the currently confirmed T1D loci, that have been discovered and replicated mostly in diverse populations, are common to all European populations. The observed effect modifications by subgrouping require validation in later studies with more statistical power.

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Objective: We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity. Methods: Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes (T1D) from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A); and genotyped for HLA DR/DQ alleles. In the DIPP study, autoantibodies were regularly analyzed from birth up to 15 years of age. Results: In the DIPP cohort, 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268, and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody, whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR. Conclusions: These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response.

The northwestern flank of the Slavic expanse of settlement, the territory of today's Russian Karelia, constitutes an age-old site of Slavic-Baltic-Finnic contact. The Karelians and Vepsians, two Finno-Ugrian groups, are a part of the indigenous population of Karelia. The settlements of the former are found mainly in the western half of the present-day Karelian Republic. The Vepsians live on the southwestern coastal strip of Lake Onega, south of the capital of the republic, Petrozavodsk. Vepsian settlements are also found outside Karelia, in Vologda and Leningrad provinces. For several centuries, the Russians have formed a majority of the inhabitants both near Lake Onega and on the west coast of the White Sea. In contrast to the Karelians, Vepsians and Russians, Finns can be considered newcomers to Karelia.