The Journal of clinical endocrinology and metabolism · 2020
Amino Acid Polymorphisms in Hla Class II Differentiate Between Thyroid and Polyglandular Autoimmunity.
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Frommer Lara, Flesch Brigitte K, König Jochem, Kahaly George J
Аннотация
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.
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.