期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 24, 页码 8867-8872出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1406575111
关键词
HLA imputation; autoinflammation; antigen presentation; killer immunoglobulin-like receptors; natural killer cells
资金
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Human Genome Research Institute of the National Institutes of Health (NIH)
- Istanbul University Research fund
- NIH [N1R01AR062886-01]
- Netherlands Organization for Scientific Research [016.126.354]
The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Behcet disease (BD). Associations between BD and other factors within the MHC have been reported also, although strong regional linkage disequilibrium complicates their confident disentanglement from HLA-B*51. In the current study, we examined a combination of directly obtained and imputed MHC-region SNPs, directly obtained HLA-B locus types, and imputed classical HLA types with their corresponding polymorphic amino acid residues for association with BD in 1,190 cases and 1,257 controls. SNP mapping with logistic regression of the MHC identified the HLA-B/MICA region and the region between HLA-F and HLA-A as independently associated with BD (P < 1.7 x 10(-8)). HLA-B*51, -A*03, -B*15, -B*27, -B*49, -B*57, and -A*26 each contributed independently to BD risk. We directly examined rs116799036, a noncoding SNP upstream of HLA-B that was recently suggested to underlie the association of HLA-B*51 with BD, but we were unable to replicate that finding in our collection. Instead, we mapped the BD association to seven MHC class I (MHC-I) amino acid residues, including anchor residues that critically define the selection and binding of peptides to MHC-I molecules, residues known to influence MHC-I-killer immunoglobulin-like receptor interactions, and a residue located in the signal peptide of HLA-B. The locations of these variants collectively implicate MHC-I peptide binding in the pathophysiology of BD. Furthermore, several lines of evidence suggest a role for altered regulation of cellular cytotoxicity in BD pathogenesis.
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