Beh?et disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

Michael J. Ombrello; Yohei Kirino; Paul I. W. de BakkerAhmet GülDaniel L. KastnerElaine F. Remmers

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Beh?et disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

机译：Beh?et disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

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The HLA protein, HLA-B*51, encoded by HLA-B in MHC, is the strongest known genetic risk factor for Beh?et 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 × 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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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第24期|8867-8872|共6页
作者
Michael J. Ombrello; Yohei Kirino; Paul I. W. de BakkerAhmet GülDaniel L. KastnerElaine F. Remmers;
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作者单位

Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892;

Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;

Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
HLA imputation; autoinflammation; antigen presentation; killer immunoglobulin-like receptors; natural killer cells;

Beh?et disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity

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