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Genetic association study of NF-?B genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy.

ABSTRACT: OBJECTIVE:Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-? is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-?B). Several genes share homology with the NF-?B family of proteins. This study investigated the role of NF-?B-related genes in disease susceptibility in UK Caucasian IIM. METHODS:Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-?B-related genes. Data were stratified by IIM subgroup/serotype. RESULTS:A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P?=?0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D'?=?1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08. CONCLUSION:An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-?B genes therefore do not independently confer susceptibility in IIM.

SUBMITTER: Chinoy H

PROVIDER: S-EPMC3327167 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Genetic association study of NF-κB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy.

Chinoy Hector H Li Charles K-C CK Platt Hazel H Fertig Noreen N Varsani Hemlata H Gunawardena Harsha H Betteridge Zoe Z Oddis Chester V CV McHugh Neil J NJ Wedderburn Lucy R LR Ollier William E R WE Cooper Robert G RG

Rheumatology (Oxford, England) 20111230 5

<h4>Objective</h4>Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM.<h4>Methods</h4>Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) ...[more]

PMID: 22210660

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Project description:Background: Systemic-Onset Juvenile Idiopathic Arthritis (SJIA) is a rare disease associated with dysregulated interleukin (IL)-1 activity. Objectives: To assess the efficacy and safety of Anakinra, an IL-1 receptor antagonist in SJIA and its effects on gene expression profiling. Methods: We conducted a multicenter, randomized, double-blind placebo-controlled trial. The primary objective was to compare the efficacy of a one-month treatment with anakinra (2 mg/kg subcutaneoulsy daily, maximum 100 mg) to a placebo between 2 groups of 12 SJIA patients each. Response was defined by a 30% improvement of the pediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared to baseline. An intention-to-treat analyze was performed. After Month 1 (M1), patients taking placebo were switched to Anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months. Results: At M1, concluding the randomized trial, there was a significant difference in the response rate between patients treated with Anakinra (8/12 responders) and placebo (1/12) (p=0.003). The number of adverse events, mainly pain to injections, was similar between both groups. Ten patients from the placebo group switched to Anakinra at M1; nine were responders at M2. Between M1 and M12, six patients stopped treatment for an adverse event (Crohn’s disease, hepatitis), a lack of efficacy or a disease flare (2 cases each). Blood gene expression profiling at enrollment and upon follow-up allowed us to identify one set of dysregulated genes that reverted to normal values in the clinical responders and a second set, including interferon-inducible genes, that was induced by Anakinra. Conclusion: Anakinra is an effective treatment of SJIA. Its effect is associated with normalization of blood gene expression profiles in clinical responders and de novo induction of an interferon signature. (Clinical trials registration number: NCT00339157)

Dataset Information

Genetic association study of NF-?B genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy.

Publications

Genetic association study of NF-κB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy.

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