Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease

Maria Wilbe; Sergey V Kozyrev; Fabiana H G Farias; Hanna D Bremer; Anna Hedlund; Gerli R Pielberg; Eija H Seppälä; Ulla Gustafson; Hannes Lohi; Örjan Carlborg; Göran Andersson; Helene Hansson-Hamlin; Kerstin Lindblad-Toh

doi:10.1371/journal.pgen.1005248

Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease

PLoS Genet. 2015 Jun 9;11(6):e1005248. doi: 10.1371/journal.pgen.1005248. eCollection 2015 Jun.

Affiliations

¹ Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
² Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
³ Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
⁴ Research Programs Unit, Molecular Neurology; Department of Veterinary Biosciences, University of Helsinki and Folkhälsan Research Center, Helsinki, Finland.
⁵ Department of Clinical Sciences, Division of Computational Genetics, Swedish University of Agricultural Sciences (SLU), Uppsala, Sweden.
⁶ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Broad Institute, Cambridge, Cambridge, Massachusetts, United States of America.

Abstract

The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAMTOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Case-Control Studies
Dogs
Genetic Loci
Genome*
Haplotypes
Lupus Erythematosus, Systemic / genetics*
Lupus Erythematosus, Systemic / veterinary
Phenotype*

Grants and funding

The work was supported by the Foundation of Thure F and Karin Forsberg, the Swedish Kennel Club, the Swedish insurance company Agria, FORMAS, the Swedish Research Council and the King Gustaf V:80 years fund. Sequencing was performed by the SNP&SEQ Technology Platform in Uppsala, which is supported by Uppsala University, Uppsala University Hospital and Science for Life Laboratory Uppsala and the Swedish Research Council (Contracts 80576801 and 70374401). ÖC and KLT were funded by a EURYI award from ESF and ÖC was funded by a Future Research Leader grant from the Swedish Foundation for Strategic Research (SSF). FHGF was funded by a fellowship from Svenska Institutet. MW was partly funded by a scholarship from Lennanders stiftelse. HL and EHS were partly supported by the Academy of Finland, the Sigrid Juselius Foundation and Biocentrum Helsinki. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.