title: Gene-gene-sex interaction in cytokine gene polymorphisms revealed by serum interferon alpha phenotype in juvenile dermatomyositis.
abstract: OBJECTIVE
  To detect genetic polymorphisms associated with high serum interferon alpha (IFN-alpha) levels in juvenile dermatomyositis (JDM) and explore interactions in associated polymorphisms.
  
  
  METHODS
  Eighty-five children of European ancestry with definite/probable JDM were studied. Selected genetic polymorphisms that were associated with high IFN-alpha levels in 12 untreated patients with newly diagnosed JDM were genotyped in a validation cohort of 73 children with JDM and analyzed for gene-gene and gene-sex interactions.
  
  
  RESULTS
  Untreated children with newly diagnosed JDM carrying both the osteopontin (OPN) rs28357094G and tumor necrosis factor alpha (TNF-alpha)-308 A alleles had significantly increased serum IFN-alpha levels. These 2 polymorphisms were genotyped in the validation cohort, and the OPN rs28357094G allele was more common in female subjects with JDM (odds ratio=3.97, P=.012). This OPN allele was most strongly enriched in female carriers of TNF-alpha-308A as compared with male carriers of TNF-alpha-308A (odds ratio>9.0; P=7.2x10(-3)).
  
  
  CONCLUSIONS
  These data support a complex gene-gene-sex interaction between the OPN and TNF-alpha promoter regions in JDM, defining a high serum IFN-alpha subgroup within JDM. This suggests pathogenic synergy between the OPN and TNF-alpha loci in female subjects with JDM, which may underlie some of the increased incidence of this condition in girls.
authors.affiliation: Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Pritzker School of Medicine, Chicago, IL 60637, USA. tniewold@medicine.bsd.uchicago.edu
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
authors.forename: Silvia N
authors.initials: SN
authors.lastname: Kariuki
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Morgan
authors.forename: Sheela
authors.initials: S
authors.lastname: Shrestha
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Pachman
mesh_terms: D002648:Child; D003882:Dermatomyositis / Q000097:blood* / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D016898:Interferon-alpha / Q000097:blood* / Q000235:genetics*; D008297:Male; D053495:Osteopontin / Q000097:blood / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012737:Sex Factors
chemical_list: D016898:Interferon-alpha; D053495:Osteopontin