Original Article
Gene-Gene-Sex Interaction in Cytokine Gene Polymorphisms Revealed by Serum Interferon Alpha Phenotype in Juvenile Dermatomyositis

https://doi.org/10.1016/j.jpeds.2010.04.034Get rights and content

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.

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

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      The top susceptibility genes in European ancestry patients include the PNP rs7897633 risk variant, a loss-of-function polymorphism that induces IFN-1 pathway activation in lymphocytes (Ghodke-Puranik et al., 2017), and the PRKG1 rs7897633 variant, for which mechanistic studies are needed to elucidate the connection to IFN-1 production and signaling. Polymorphisms in various genes associated with high IFN-1 activity in SLE have also been found in association with increased circulating IFN-α levels in juvenile DM, including the osteopontin (or SPP1) and TNF-α-308 G/A variants (Kariuki et al., 2009b; Niewold et al., 2010). Gene variants affecting IFN-1 downstream signaling pathways have also been described.

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      OPN gene polymorphisms associate with autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, and plasma OPN concentration is correlated with systemic lupus erythematosus susceptibility, serum cytokine profiles, and disease activity (Forton et al., 2002; Wong et al., 2005; Han et al., 2008; Kariuki et al., 2009). A polymorphism for OPN in a cohort of newly diagnosed juvenile DM patients was associated with increased serum IFN-α level (Niewold et al., 2010). Demonstrated immunological functioning of OPN includes polyclonal B cell and macrophage activation in autoimmune murine models and activation-induced T-cell death (Singh et al., 1990; Lampe et al., 1991; Weber and Cantor, 2001; Chiocchetti et al., 2004).

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    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.

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