TY - JOUR
T1 - Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease
AU - Wilbe, Maria
AU - Kozyrev, Sergey V.
AU - Farias, F.H.G.
AU - Bremer, Hanna
AU - Hedlund, A.
AU - Pielberg, Gerli
AU - Seppälä, Eija H.
AU - Gustafson, Ulla
AU - Lohi, Hannes
AU - Carlborg, Örjan
AU - Andersson, Göran
AU - Hansson-Hamlin, Helene
AU - Lindblad-Toh, Kerstin
PY - 2015
Y1 - 2015
N2 - 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 (ANAH) and speckled ANA (ANAS) 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.
AB - 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 (ANAH) and speckled ANA (ANAS) 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.
KW - Systemic-Lupus-Erythematosus
KW - responsive meningitis-arteritis
KW - Domain-peptide complex
KW - BANK1 gene
KW - Kawasaki-disease
KW - Pain syndrome
KW - Susceptibility
KW - Systemic-Lupus-Erythematosus
KW - responsive meningitis-arteritis
KW - Domain-peptide complex
KW - BANK1 gene
KW - Kawasaki-disease
KW - Pain syndrome
KW - Susceptibility
UR - https://res.slu.se/id/publ/69259
U2 - 10.1371/journal.pgen.1005248
DO - 10.1371/journal.pgen.1005248
M3 - Journal article
C2 - 26057447
SN - 1553-7390
VL - 11
JO - PLOS Genetics
JF - PLOS Genetics
IS - 6
M1 - e1005248
ER -