Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis.
Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM.



The study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR.



Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2×10(-6)). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients.



Complement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background.
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Katherine E
KE
Lintner
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Anjali
A
Patwardhan
Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Lisa G
LG
Rider
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Rabheh
R
Abdul-Aziz
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Yee Ling
YL
Wu
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
Emeli
E
Lundström
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden.
Leonid
L
Padyukov
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Bi
B
Zhou
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Alaaedin
A
Alhomosh
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
David
D
Newsom
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Peter
P
White
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Karla B
KB
Jones
Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Terrance P
TP
O'Hanlon
Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, Maryland, USA.
Frederick W
FW
Miller
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Charles H
CH
Spencer
Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Chack Yung
CY
Yu
D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003181:Complement C4 / Q000172:deficiency / Q000235:genetics*; D015934:Complement C4a / Q000172:deficiency* / Q000235:genetics; D015935:Complement C4b / Q000235:genetics; D056915:DNA Copy Number Variations; D003882:Dermatomyositis / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics; D000081208:Hereditary Complement Deficiency Diseases; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008297:Male; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000097:blood / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics
D003181:Complement C4; D059811:HLA-DRB1 Chains; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506033:TNFRSF25 protein, human; D015934:Complement C4a; D015935:Complement C4b
Autoimmune Diseases; Dermatomyositis; Disease Activity; Epidemiology; Gene Polymorphism