HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes

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.

Fig 1. Groups of comparison used for the analyses.

The children with multiple autoimmune diseases (AIDs) were compared with children with type 1 diabetes (T1D) only, and the children from autoimmune families to a group of children with T1D only and without any first- or second-degree relatives with any known AIDs. *Autoimmune families: ≥4 diagnoses of AIDs (T1D or other) and/or ≥3 different AIDs (T1D or other) in first- and/or second-degree relatives and/or the index child.

Fig 2. Combined mean number of risk alleles per subject compared between the groups.

Mean number of risk alleles (0, 1, or 2 per SNP) were compared between children with type 1 diabetes only and children with multiple autoimmune diseases left, P = 0.39), and children without any family history of autoimmune disease and children from autoimmune families (≥4 diagnoses of autoimmune diseases and/or ≥3 different autoimmune diseases in the extended family, right, P = 0.38).