Session Type: ACR Concurrent Abstract Session
Session Time: 9:00AM-10:30AM
Host genetics influence susceptibility to Kawasaki disease (KD), an acute pediatric vasculitis, and genome wide association studies (GWAS) have detected variants with modest effects on disease susceptibility. Recently we performed a pathway analysis using a European descent KD GWAS dataset. We reported that the antigen processing and presentation pathway was one of the top 50 pathways associated with KD susceptibility with 9 single nucleotide variants (SNVs) located near HLA-B and C in the HLA class I region driving the association. We speculated that these SNVs in the HLA class I region influence antigen presentation and KD susceptibility.
Nine SNVs in the HLA region from our European descent GWAS were tested for association with KD using a Japanese GWAS dataset. To explore the influence of these SNVs on KD susceptibility, we performed expression quantitative trait loci (eQTL) analysis using a US multi-ethnic cohort (n=146) and analyzed the associated polymorphic amino acid sequence of HLA-B and –C by HLA typing an independent U.S. multi-ethnic cohort (n=78) and a Japanese cohort (subset of Japanese GWAS n=275).
Two SNVs (rs6906846 upstream of HLA-C and rs2254556 upstream of HLA-B) were significantly associated with KD susceptibility in both the European descent and Japanese GWAS datasets (combined nominal p=1.0xE-04 for rs6906846 and p=7.0xE-05 for rs2254556). HLA typing in both our U.S. multi-ethnic cohort (n=78) and the Japanese cohort (n=275) revealed association of the risk allele at this locus with specific HLA-C types (e.g. HLA-C*07:02 U.S. and Japanese combined p=2.8xE-30) and with specific amino acid sequences at multiple HLA-C positions, including several in the peptide binding groove that could influence peptide binding and presentation. The risk allele (A) at rs6906846 was associated with higher expression of HLA-C by microarray (n=146, AA vs. GG p<1.0xE-04) and targeted amplification of whole blood RNA in an independent U.S. multi-ethnic cohort (n=42, AA vs. GG p<5.0xE-02). We extended the eQTL analysis using our U.S. multi-ethnic array data (n=146) to 5 previously reported SNVs associated with KD that were located in/near genes in the HLA class I pathway from the Japanese GWAS: rs2854251 (proximal to antigen peptide transporter (TAP) 1/2 and proteasome subunit beta (PSMB) 8/9) and a Taiwanese GWAS: rs149481 (Endoplasmic reticulum aminopeptidase (ERAP)1/2 region), and rs1873668, rs4243399, and rs16849083 (coatomer protein complex subunit beta 2 (COPB2) region). In our U.S. multi-ethnic cohort (n=146), we found increased transcript levels of TAP2 (GG vs. AA p<5.0xE-03) and PSMB8 (GG vs. AA p<5.0xE-02), and reduced ERAP2 transcripts (AA vs. AC p<5.0xE-03) associated with the corresponding risk alleles.
Conclusion: SNVs that influence the amino acid sequence in the HLA peptide binding groove and that serve as eQTL for HLA-C pathway proteins influence KD susceptibility in diverse ethnic groups. These findings suggest the importance of HLA-C antigen presentation to CD8+ T cells and/or NK cell regulation in KD pathogenesis.
To cite this abstract in AMA style:Shimizu C, Kim J, Eleftherohorinou H, Wright V, Hoang L, Tremoulet A, Franco A, Hibberd M, Takahashi A, Kubo M, Ito K, Tanaka T, Onouchi Y, Coin L, Levin M, Burns J, Shike H. Genetic Variants in HLA-C and Class I Pathway Genes Influence Susceptibility to Kawasaki Disease [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/genetic-variants-in-hla-c-and-class-i-pathway-genes-influence-susceptibility-to-kawasaki-disease/. Accessed August 13, 2020.
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