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

Anna Parkkola; Antti-Pekka Laine; Markku Karhunen; Taina Härkönen; Samppa J Ryhänen; Jorma Ilonen; Mikael Knip; Finnish Pediatric Diabetes Register

doi:10.1371/journal.pone.0188402

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

PLoS One. 2017 Nov 28;12(11):e0188402. doi: 10.1371/journal.pone.0188402. eCollection 2017.

Authors

Anna Parkkola^{1

2

3}, Antti-Pekka Laine⁴, Markku Karhunen⁵, Taina Härkönen^{1

3}, Samppa J Ryhänen^{1

3}, Jorma Ilonen⁴, Mikael Knip^{1

2

3

6}; Finnish Pediatric Diabetes Register

Affiliations

¹ Scientific Laboratory, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
² Folkhälsan Research Center, Helsinki, Finland.
³ Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
⁴ Immunogenetics Laboratory, University of Turku, and Turku University Hospital, Turku, Finland.
⁵ Department of Political and Economic Studies, University of Helsinki, Helsinki, Finland.
⁶ Department of Pediatrics, Tampere University Hospital, Tampere, Finland.

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.

MeSH terms

Autoimmune Diseases / genetics*
Child
Child, Preschool
Diabetes Mellitus, Type 1 / genetics*
Female
Genetic Predisposition to Disease*
HLA Antigens / genetics*
Haplotypes
Humans
Male
Polymorphism, Single Nucleotide

Substances

HLA Antigens

Grants and funding

This work was supported by the Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, Decision No. 250114 and Decision No. 250124) (MK), the Sigrid Jusélius Foundation (MK), the Novo Nordisk Foundation (MK), the Liv and Hälsa Fund (MK), the Finnish Medical Foundation (AP), the Biomedicum Helsinki Foundation (AP), and the National Graduate School of Clinical Investigation (AP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.