220-P: Examination of HLA class II amino acid variation in juvenile idiopathic arthritis (JIA) implicates P4 with position 86

Abstract Intron-22-inversion patients express the entire Factor VIII (FVIII)-amino-acid sequence intracellularly as 2 non-secreted polypeptides and have a positive “intracellular (I)-FVIII-CRM” status. Mutations conferring a positive I-FVIII-CRM status are associated with low inhibitor risk and are pharmacogenetically relevant because inhibitor risk may be affected by the nature of the therapeutic FVIII-protein (tFVIII), the affinity of any tFVIII-derived foreign peptide (tFVIII-fp) for any HLA class-II isomer (HLA-II) comprising individual major histocompatibility complex (MHC) repertoires, and the stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely or substantially negative I-FVIII-CRM status are pharmacogenetically irrelevant because inhibitor risk is high with any tFVIII and individual MHC repertoire.

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Different Distribution of HLA Class II Alleles in Anti-Topoisomerase I Autoantibody Responders between Silicosis and Systemic Sclerosis Patients, with a Common Distinct Amino Acid Sequence in the HLA-DQB1 Domain

Immunobiology ◽

10.1078/0171-2985-00055 ◽

2001 ◽

Vol 204 (4) ◽

pp. 458-465 ◽

Cited By ~ 31

Author(s):

A UEKI

Keyword(s):

Systemic Sclerosis ◽

Amino Acid ◽

Amino Acid Sequence ◽

Topoisomerase I ◽

Class Ii ◽

Hla Class Ii ◽

Hla Class Ii Alleles

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Amino Acid Polymorphisms in Hla Class II Differentiate Between Thyroid and Polyglandular Autoimmunity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz164 ◽

2019 ◽

Vol 105 (6) ◽

pp. 1737-1747 ◽

Cited By ~ 2

Author(s):

Lara Frommer ◽

Brigitte K Flesch ◽

Jochem König ◽

George J Kahaly

Keyword(s):

Monte Carlo ◽

Amino Acid ◽

Peptide Binding ◽

Class Ii ◽

Hla Class Ii ◽

Exon 2 ◽

Allele Distribution ◽

Autoimmune Thyroid ◽

The Impact ◽

Polyglandular Autoimmunity

Abstract Context The structure of the human leucocyte antigen (HLA) peptide-binding clefts strongly contributes to monoglandular and polyglandular autoimmunity (AP). Objective To investigate the impact of amino acid polymorphisms on the peptide-binding interactions within HLA class II and its association with AP. Design Immunogenetic study. Setting Tertiary referral center for autoimmune endocrine diseases. Subjects 587 subjects with AP, autoimmune thyroid disease (AITD), type 1 diabetes (T1D), and healthy unrelated controls were typed for HLA class II. Methods Amino acids within the peptide binding cleft that are encoded by HLA class II exon 2 were listed for all codon positions in all subjects. Overall comparisons between disease and control groups with respect to allele distribution at a given locus were performed by assembling rare alleles applying an exact Freeman Halton contingency table test with Monte-Carlo P values based on 150 000 samples. Results The Monte Carlo exact Fisher test demonstrated marked differences in all 3 loci, DQA1, DQB1, and DRB1 (P < .0001) between AP and both AITD and controls, as well as between AP type II (Addison’s disease as a major endocrine component) and AP type III (T1D + AITD). Differences were also noted between AP and T1D pertaining to the DRB1 allele (P < .041). Seven amino acid positions, DRB1-13, DRB1-26, DRB1-71, DRB1-74, DQA1-47, DQA1-56, and DQB1-57, significantly contributed to AP. Five positions in DQA1 (11, 47, 50, 56, and 69) completely correlated (P < .0001). Conclusion Amino acid polymorphisms within HLA class II exon 2 mediate the AP risk and differentiate between thyroid and polyglandular autoimmunity.

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Evolution of HLA Class II Molecules: Allelic and Amino Acid Site Variability Across Populations

Genetics ◽

10.1093/genetics/152.1.393 ◽

1999 ◽

Vol 152 (1) ◽

pp. 393-400 ◽

Cited By ~ 1

Author(s):

Hugh Salamon ◽

William Klitz ◽

Simon Easteal ◽

Xiaojiang Gao ◽

Henry A Erlich ◽

...

Keyword(s):

Amino Acid ◽

Acid Site ◽

Balancing Selection ◽

Amino Acid Level ◽

Class Ii ◽

Acid Sites ◽

Hla Class Ii ◽

Amino Acid Site ◽

Significant Difference ◽

Hla Class Ii Molecules

Abstract Analysis of the highly polymorphic β1 domains of the HLA class II molecules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele frequency distributions, based on Watterson’s homozygosity statistic F, reveal distinct evolutionary patterns for these loci in ethnically diverse samples (26 populations for DQB1 and DRB1 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balanced polymorphism (P < 10-4), DRB1 shows some evidence of balancing selection (P < 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P < 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over polymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutrality expectations, and both exhibit more balanced polymorphic amino acid sites than DRB1. Across ethnic groups, polymorphisms at many codons show evidence for balancing selection, yet data consistent with directional selection were observed at other codons. Both antigen-binding pocket- and non-pocket-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference between pocket- and non-pocket-forming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic amino acid residues, and that in many cases this selection is consistent across populations.

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