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
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Cited by (31)
Type I Interferons in Autoimmunity
2022, Journal of Investigative DermatologyCitation Excerpt :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.
Advances in Juvenile Dermatomyositis: Myositis Specific Antibodies Aid in Understanding Disease Heterogeneity
2018, Journal of PediatricsCitation Excerpt :As in systemic lupus erythematosus, some children with JDM have decreased gene copy number for C4 (A > B), resulting in low production of C4,14 which may also be diminished by complement consumption. The increase incidence of JDM in girls appears to be associated with a synergy between osteopontin and the tumor necrosis factor (TNF)-α locus.15 A range of potential facilitating factors are under active consideration: seasonality of birth; sun/UVB exposure; prenatal smoke/pollution exposure; urban vs rural dwelling; life stressor; and immunizations and medications.
Cytokines in lupus
2018, Dubois' Lupus Erythematosus and Related SyndromesThe type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases
2016, GeneCitation Excerpt :Many of these IFN-induced genes are similar to those which are upregulated in SLE. Also, studies have suggested a genetic or heritable component to the high type I IFN levels observed in this disease, similar to seen in SLE (Niewold et al., 2010; Niewold et al., 2011). The expression of the type I IFN-inducible genes in dermatomyositis (DM) also correlates positively with disease activity and with titers of anti-Jo1 and anti-Ro autoantibodies, which can be observed in this disease (Baechler et al., 2007; Niewold et al., 2009).
Gene×gene×gender interaction of BDNF and COMT genotypes associated with panic disorder
2014, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :There are few previous studies of gene–gene interactions related to gender differences. Niewold et al. (2010) reported a gene–gene–sex interaction in cytokine gene polymorphisms in juvenile dermatomyositis; to the best of our knowledge, such an interaction has not yet been reported in psychiatric disease. We studied the gene × gene × gender interaction of BDNF and COMT genotypes associated with panic disorder, and we suspect that the gender specificity of COMT Val158Met influences personality traits in male PD patients.
Gottron's papules exhibit dermal accumulation of CD44 variant 7 (CD44v7) and its binding partner osteopontin: A unique molecular signature
2012, Journal of Investigative DermatologyCitation Excerpt :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).
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.