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Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4

Kejian Zhang1, Jennifer Biroschak, David N Glass

  • 1Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Arthritis and Rheumatism
|September 2, 2008
PubMed
Abstract

Insights

Genetic variations in MUNC13-4 are linked to macrophage activation syndrome in systemic juvenile idiopathic arthritis (JIA). This study investigated MUNC13-4 sequence alterations in patients with systemic JIA and macrophage activation syndrome.

Area of Science:

  • Immunology
  • Genetics
  • Pediatric Rheumatology

Background:

  • Systemic juvenile idiopathic arthritis (JIA) is frequently complicated by macrophage activation syndrome (MAS).
  • Macrophage activation syndrome shares clinical similarities with familial hemophagocytic lymphohistiocytosis (HLH).
  • Mutations in the MUNC13-4 gene have been recently identified as a cause of familial HLH.

Purpose of the Study:

  • To investigate potential sequence alterations in the MUNC13-4 gene in patients diagnosed with systemic JIA and MAS.
  • To explore the association between MUNC13-4 genetic variations and the development of MAS in systemic JIA.

Main Methods:

  • MUNC13-4 gene sequence analysis was performed on 18 patients with systemic JIA/MAS.
  • DNA from 73 patients with systemic JIA without MAS and 229 healthy individuals served as controls.
  • The MUNC13-4 sequence was analyzed using 32 primer pairs targeting 32 exons and adjacent intronic regions.

Main Results:

  • Biallelic MUNC13-4 sequence variants, previously linked to familial HLH, were found in 2 of 18 patients.
  • An extended haplotype of 12 single-nucleotide polymorphisms (SNPs) in MUNC13-4 was identified in 56% of the remaining patients.
  • This haplotype was significantly more prevalent in patients with systemic JIA/MAS (56%) compared to healthy controls (12%) and JIA patients without MAS (8.2%).

Conclusions:

  • The findings suggest a significant association between MUNC13-4 polymorphisms and the occurrence of macrophage activation syndrome in systemic JIA.
  • These genetic variations in MUNC13-4 may contribute to the pathogenesis of MAS in the context of systemic JIA.

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