Abstract
Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first- or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families.
Highlights
With prevalence of up to 9%, autoimmune diseases (AID) constitute a significant disease burden [1]
The other AIDs diagnosed in these children were celiac disease (n = 29), autoimmune thyroid disease (n = 24), rheumatoid arthritis (n = 4), vitiligo (n = 2), alopecia (n = 2), and colitis ulcerosa (n = 1)
The risk group distribution varied between the groups; the children with type 1 diabetes (T1D) only were characterized by high prevalence of the highest risk group, and the children with multiple AIDs with a low risk group (Table 2)
Summary
With prevalence of up to 9%, autoimmune diseases (AID) constitute a significant disease burden [1]. Patients with these diseases and their relatives are at increased risk for other AIDs [1,2,3], some diseases, for example multiple sclerosis and rheumatoid arthritis, are less likely to co-occur [1, 2, 4, 5]. Human leucocyte antigen (HLA) region on chromosome 6p21 mediates the strongest risk for many AIDs [6], but with modern genome-wide association analyses the number of genetic loci associated with autoimmunity has increased to more than one hundred. Most of these have functions related to different aspects of the immune system [7]. The A allele of the PTPN22 SNP rs2476601 yields susceptibility to type 1 diabetes (T1D) and rheumatoid arthritis but protects from Crohn’s disease [11,12,13]
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