Original ArticleGene-Gene-Sex Interaction in Cytokine Gene Polymorphisms Revealed by Serum Interferon Alpha Phenotype in Juvenile Dermatomyositis
Section snippets
Methods
Genomic DNA samples from 85 children with definite/probable JDM were studied with Bohan and Peter criteria,26 and 12 of these children had a serum sample available from the time of initial diagnosis before any treatment. Sixty-two of the subjects were female and 23 were male. All the children included in the study were of self-reported European-American ancestry. European-American Ancestry All subjects had genotyping data available for the tumor necrosis factor alpha (TNF-α) -308 promoter
Genotyping
Twelve untreated children with JDM were genotyped at single nucleotide polymorphisms (SNPs) in OPN (rs11730582, rs28357094, rs6532040, and rs9138), IRF5 (rs2004640, rs3807306, rs10488631, and rs2280714), and PTPN22 (rs2476601). Seventy-three additional children with JDM were genotyped at the OPN rs28357094 SNP. Each of these SNPs conformed to Hardy-Weinberg equilibrium (P ≥ .01 for all markers). The IRF5 rs2004640, rs3807306, rs10488631, and rs2280714 SNPs were chosen because they designate a
Results
We examined a number of genetic polymorphisms in untreated patients with JDM to detect genotype-IFN-α relationships. The TNF-α -308 A allele was significantly associated with increased serum IFN-α level. When the other SNP genotypes were examined, it was apparent that the OPN rs28357094 G allele was also associated with increased serum IFN-α level, and carriers of both the TNF-α -308 and OPN rs28357094 alleles were a high IFN-α subgroup (Figure). SNPs in IRF5 and PTPN22 did not show any
Discussion
In this study, we demonstrate that simultaneous presence of the TNF-α-308 A allele and the OPN rs28357094 G allele was associated with increased serum IFN-α activity in untreated patients with JDM of European ancestry. Similar to OPN genetic studies in SLE,20, 25 the OPN rs28357094 SNP demonstrated significant skewing of association by sex in our study. The particular allele of OPN we find to be associated with sex in children with JDM is different from the 1 in which a sex effect is observed
References (34)
- et al.
Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood
Lancet
(2008) - et al.
Molecular genetic studies of major histocompatibility complex genes in children with juvenile dermatomyositis: increased risk associated with HLA-DQA1 *0501
Hum Immunol
(1991) - et al.
MxA gene expression in juvenile dermatomyositis peripheral blood mononuclear cells: association with muscle involvement
Clin Immunol
(2006) - et al.
Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians
Arthritis Rheum
(2006) - et al.
TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications
Arthritis Rheum
(2000) - et al.
Immune interferon in the circulation of patients with autoimmune disease
N Engl J Med
(1979) Type I interferon in systemic lupus erythematosus
Curr Top Microbiol Immunol
(2007)- et al.
Activation of the type I interferon system in primary Sjogren's syndrome: a possible etiopathogenic mechanism
Arthritis Rheum
(2005) - et al.
Serum type I interferon activity is dependent on maternal diagnosis in anti-SSA/Ro-positive mothers of children with neonatal lupus
Arthritis Rheum
(2008) - et al.
An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity
Mol Med
(2007)
Elevated serum interferon-alpha activity in juvenile dermatomyositis: associations with disease activity at diagnosis and after thirty-six months of therapy
Arthritis Rheum
Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis
Arthritis Rheum
Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease
Arthritis Rheum
Gene expression profiling in DQA1*0501+ children with untreated dermatomyositis: a novel model of pathogenesis
J Immunol
Duration of chronic inflammation alters gene expression in muscle from untreated girls with juvenile dermatomyositis
BMC Immunol
High serum IFN-alpha activity is a heritable risk factor for systemic lupus erythematosus
Genes Immun
Age- and sex-related patterns of serum interferon-alpha activity in lupus families
Arthritis Rheum
Cited by (0)
Supported by National Institutes of Health/National Institute of Allergy and Infectious Disease K08 Award AI083790, National Institute of Allergy and Infectious Disease Clinical Research Loan Repayment AI071651, Clinical and Translational Science Award Collaborative Pilot Grant from UL1 RR024999, Arthritis National Research Foundation Eng Tan Scholar Award, Alliance for Lupus Research, and Lupus Research Institute Novel Research Grant (T.N.), National Institute of Arthritis, Musculoskeletal, and Skin Diseases RO-1 AR48289, the CureJM Foundation, and Macy's Miracle Foundation (L.P). The authors declare no conflicts of interest.