Gene-gene-sex interaction in cytokine gene polymorphisms revealed by serum interferon alpha phenotype in Juvenile dermatomyositis

Objective: To detect genetic polymorphisms associated with high serum interferon alpha (IFN-α) levels in juvenile dermatomyositis (JDM) and explore interactions in associated polymorphisms. Study design: Eighty-five children of European ancestry with definite/probable JDM were studied. Selected genetic polymorphisms that were associated with high IFN-α 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-α)-308 A alleles had significantly increased serum IFN-α 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-α -308A as compared with male carriers of TNF-α -308A (odds ratio >9.0; P = 7.2 x 10^-3). Conclusion: These data support a complex gene-gene-sex interaction between the OPN and TNF-α promoter regions in JDM, defining a high serum IFN-α subgroup within JDM. This suggests pathogenic synergy between the OPN and TNF-α loci in female subjects with JDM, which may underlie some of the increased incidence of this condition in girls.