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HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease

Authors
  • Shimizu, C
  • Kim, J
  • Eleftherohorinou, H
  • Wright, VJ
  • Hoang, LT
  • Tremoulet, AH
  • Franco, A
  • Hibberd, ML
  • Takahashi, A
  • Kubo, M
  • Ito, K
  • Tanaka, T
  • Onouchi, Y
  • Coin, LJM
  • Levin, M
  • Burns, JC
  • Shike, H
  • kawasaki, international
Publication Date
Apr 27, 2019
Source
Spiral - Imperial College Digital Repository
Keywords
Language
English
License
Unknown

Abstract

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a "KD peptide" that contributes to the vasculitis of KD in genetically susceptible children.

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