Transmission disequilibrium analysis of 31 type 1 diabetes susceptibility loci in Finnish families

Abstract

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.

Non-HLA gene effects on the disease process of type 1 diabetes: From HLA susceptibility to overt disease

“…The PTPN2 gene was most conspicuously affecting this rate in our study, in which homozygosity for the rs45450798C allele was strongly associated with rapid disease progression, although no effect on autoantibody seroconversion was seen. Homozygosity for the minor allele is relatively rare but it was clearly associated with the highest risk for type 1 diabetes also by Smyth et al [39], and in our family trio transmission study [40]. In contrast, the recent report by Steck et al did not observe any effect of a PTPN2 SNP in tight linkage disequilibrium with the one in our analysis during the progression from b-cell autoimmunity to clinical disease but the number of subjects with islet autoimmunity in their study was too low to detect a minor allele homozygosity effect [23].…”

“…We could not detect any significant effect of the ERBB3-IKZF4 region on the disease pathogenesis in the whole cohort analyzed although it was highly significant in the Finnish type 1 diabetes trio family analysis [40]. However, after the primary analyses we proceeded to see whether the effect of the diabetes riskassociated SNPs is related to the triggering autoantigen.…”

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility

“…Rapid progressors carrying the high-risk HLA genotype have an increased prevalence of homozygosity for the major G allele of a SNP within the FUT2 gene, although not the FUT2 SNP predisposing to type 1 diabetes, which is intriguing [15,34]. The FUT2 gene determines human secretor status by encoding 1,2-α-fucosyltransferase (FUT2), an enzyme responsible for the synthesis of soluble ABO histo-blood group antigens, which are present in bodily fluids and on intestinal mucosa [35].…”

“…SNPs of 25 non-HLA genes predisposing to type 1 diabetes were analysed to assess associations with rapid disease progression (electronic supplementary material [ESM] Table 1) [10][11][12][13][14]. SNP genotyping was performed using the Sequenom (San Diego, California, USA) platform at the Genome Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland, and was considered successful when the failure rate for the SNP marker analysis was <10% [15].…”

Insulin gene VNTR polymorphisms −2221MspI and −23HphI are associated with type 1 diabetes and latent autoimmune diabetes in adults: a meta-analysis

“…In other words, individuals with the T allele of -23HphI or the T allele of -2221MspI may be at reduced risk of T1D. However, although many candidate genes associated with T1D have been reported, the data are not completely consistent [13,16,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35]. Also, although a few studies have focused on the association between the INS VNTR and the risk of LADA, the sample sizes were small and the results were variable [15,19,33,36,37].…”