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- W2753804539 abstract "Aim The HLA-DRB1 locus represents the greatest genetic risk factor for susceptibility to rheumatoid arthritis (RA). We have cloned and expressed multiple HLA alleles and measured binding of native and citrullinated peptides on cell lines. Subsequent mutagenesis and peptide binding studies have shown that mutating lysine at position 71 of DR β 1∗04:01 (K 71 ) to the glutamic acid residue (E 71 ) found in RA-resistant alleles ( e.g. DR β 1∗01:03 and ∗04:02) completely abrogates the preferential binding of citrullinated vimentin 66-78 and citrullinated α - enolase 11 - 25 , as compared to their native forms, and eliminates binding of collagen 258 - 272 . As such, this single amino acid substitution renders the arthritogenic peptide-binding profile of DR β 1∗04:01 nearly identical to that of the resistant allele, DR β 1∗04:02. Methods We examined 488 RA patients and 448 demographically matched controls to determine if genetic inheritance of a glutamic acid at position 71 in DRB1 is protective, even if lysine is present on the second allele, and therefore dominant resistant. Age of disease onset was also correlated with the amino acid present at position 71. Results The amino acids found at position 71 were limited to lysine, alanine, arginine and glutamic acid. When both DRB1 alleles expressed lysine at position 71 (K/K), the odds ratio (OR) for RA was 2.05 ( p = 0.0465). Inheritance of R/R was also associated with susceptibility to RA (OR = 1.26). In contrast, if both alleles expressed glutamic acid (E/E), patients were protected from developing RA (OR = 0.10, p = 0.009). Importantly, individuals who inherited only one DRB1 allele with a glutamic acid at position 71 (E/A, K/E or E/R) also showed significant protection from RA (OR = 0.1, p = 0.14 and 0.55, respectively). In addition, age of disease onset was significantly later in RA patients that were heterozygous for glutamic acid at position 71. Conclusions These results demonstrate that inheritance of glutamic acid at position 71 of HLA-DRB1 is dominantly protective in RA." @default.
- W2753804539 created "2017-09-15" @default.
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- W2753804539 date "2017-09-01" @default.
- W2753804539 modified "2023-09-26" @default.
- W2753804539 title "P017 Glutamic acid at position 71 in HLA-DRB1 is dominantly protective in rheumatoid arthritis" @default.
- W2753804539 doi "https://doi.org/10.1016/j.humimm.2017.06.077" @default.
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