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

Rheumatology (Oxford). 2012 May;51(5):794-9. doi: 10.1093/rheumatology/ker379. Epub 2011 Dec 30.

Abstract

Objective: 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.

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-κB-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-κB genes therefore do not independently confer susceptibility in IIM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adolescent
  • Adult
  • Aged
  • Alleles
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • Haplotypes
  • Histocompatibility Antigens Class II / genetics*
  • Humans
  • Male
  • Middle Aged
  • Myositis / genetics*
  • NF-kappa B / genetics*
  • Polymorphism, Single Nucleotide
  • Tumor Necrosis Factor-alpha / genetics
  • United Kingdom

Substances

  • Adaptor Proteins, Signal Transducing
  • Histocompatibility Antigens Class II
  • NF-kappa B
  • NFKBIL1 protein, human
  • Tumor Necrosis Factor-alpha