Mutational profile of rare variants in inflammasome-related genes in Behçet disease: A Next Generation Sequencing approach

Sci Rep. 2017 Aug 16;7(1):8453. doi: 10.1038/s41598-017-09164-7.

Abstract

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adenosine Deaminase / genetics
  • Behcet Syndrome / genetics*
  • Cytoskeletal Proteins / genetics
  • Female
  • Genetic Predisposition to Disease / genetics*
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Inflammasomes / genetics*
  • Inflammation / genetics
  • Intercellular Signaling Peptides and Proteins / genetics
  • Male
  • Mutation*
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • Nod2 Signaling Adaptor Protein / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Pyrin / genetics
  • Receptors, Tumor Necrosis Factor, Type I / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Inflammasomes
  • Intercellular Signaling Peptides and Proteins
  • MEFV protein, human
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • PSTPIP1 protein, human
  • Pyrin
  • Receptors, Tumor Necrosis Factor, Type I
  • TNFRSF1A protein, human
  • Phosphotransferases (Alcohol Group Acceptor)
  • mevalonate kinase
  • ADA2 protein, human
  • Adenosine Deaminase