Session Title: Genetics and Genomics of Rheumatic Disease II
Session Type: Abstract Submissions (ACR)
Background/Purpose: Behçet’s Disease (BD) is a complex genetic disease of unknown etiology that is characterized by inflammatory lesions of the eyes, skin, and oro-genital mucosa. The class I major histocompatibility complex (MHC) molecule, HLA-B*51 (B*51), is the strongest known genetic risk factor for BD. Associations between BD and a range of other factors within the extended MHC locus (xMHC) have also been reported, however strong linkage disequilibrium across the xMHC has complicated the confident disentanglement of other BD risk factors from B*51.
Methods: We examined a combination of directly obtained and imputed single nucleotide polymorphism (SNP) genotypes, directly obtained HLA-B locus types, and imputed classical HLA types and polymorphic HLA amino acid residues for association with BD in 1190 BD cases and 1257 controls. Genotypes from 2832 xMHC SNPs were extracted from a genome wide SNP array, and these data were used as the basis for SNP imputation with reference data from the 1000 Genomes Project. HLA-B types were determined using a sequence specific oligonucleotide-based assay. We used imputation to infer classical HLA types and the identities of polymorphic amino acid residues in each classic HLA molecule. Stepwise logistic regression and conditional analyses were performed using genotype probabilities produced by imputation.
Results: SNP mapping of the xMHC identified two regions, the HLA-B/MICA region and the region between HLA-F and HLA-A, as independently and significantly associated with BD after respective regression analyses (p < 1.7E-08). Haplotype analysis of the HLA-B/MICA region identified a common BD-associated haplotype that included B*51 and 48 BD-associated SNPs, yet an identical SNP haplotype that lacked B*51 conferred no risk of BD. We found that HLA-B*51, –B*15, –B*27, –B*57, and –A*26 each contributed to BD risk independently, while HLA-B*49 and –A*03 were each protective against the development of BD. Regression analyses of polymorphic amino acid residues identified independent associations between BD and nine MHC class I amino acid residues, including one that conferred risk in both HLA-A and HLA-B. The majority of the BD-associated residues clustered around the MHC class I antigen binding groove, however one residue was located in the signal peptide of HLA-B. The BD-associated risk variant, threonine, at position -21 in the signal peptide has been previously shown to produce enhanced NK cell activation and cytotoxicity by reducing inhibitory NK ligand expression, when compared to the protective variant, methionine.
Conclusion: There are multiple MHC class I antigens, including B*51, that independently affect BD susceptibility. Nine MHC class I amino acid residues influence BD risk, eight of which map to the antigen binding groove and imply adaptive immune involvement. One BD-associated residue is within the HLA-B signal peptide, a known point of cross-talk between the innate and adaptive immune systems, where it leads to reduced protection from NK cytotoxicity. Together, our data indicate that MHC class I molecules influence BD risk through both innate and adaptive immune mechanisms.
M. J. Ombrello,
P. de Bakker,
E. F. Remmers,
D. L. Kastner,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/major-histocompatibility-complex-class-i-molecules-contribute-to-behcets-disease-risk-through-both-innate-and-adaptive-immune-interactions/