title: Electrostatic modifications of the human leukocyte antigen-DR P9 peptide-binding pocket and susceptibility to primary sclerosing cholangitis.
abstract: The strongest genetic risk factors for primary sclerosing cholangitis (PSC) are found in the human leukocyte antigen (HLA) complex at chromosome 6p21. Genes in the HLA class II region encode molecules that present antigen to T lymphocytes. Polymorphisms in these genes are associated with most autoimmune diseases, most likely because they contribute to the specificity of immune responses. The aim of this study was to analyze the structure and electrostatic properties of the peptide-binding groove of HLA-DR in relation to PSC. Thus, four-digit resolution HLA-DRB1 genotyping was performed in 356 PSC patients and 366 healthy controls. Sequence information was used to assign which amino acids were encoded at all polymorphic positions. In stepwise logistic regressions, variations at residues 37 and 86 were independently associated with PSC (P = 1.2 × 10(-32) and P = 1.8 × 10(-22) in single-residue models, respectively). Three-dimensional modeling was performed to explore the effect of these key residues on the HLA-DR molecule. This analysis indicated that residue 37 was a major determinant of the electrostatic properties of pocket P9 of the peptide-binding groove. Asparagine at residue 37, which was associated with PSC, induced a positive charge in pocket P9. Tyrosine, which protected against PSC, induced a negative charge in this pocket. Consistent with the statistical observations, variation at residue 86 also indirectly influenced the electrostatic properties of this pocket. DRB1*13:01, which was PSC-associated, had a positive P9 pocket and DRB1*13:02, protective against PSC, had a negative P9 pocket.
  
  
  CONCLUSIONS
  The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DRβ chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented.
authors.affiliation: Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Hov
authors.forename: Vasilis
authors.initials: V
authors.lastname: Kosmoliaptsis
authors.forename: James A
authors.initials: JA
authors.lastname: Traherne
authors.forename: Marita
authors.initials: M
authors.lastname: Olsson
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Boberg
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Taylor
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D020816:Amino Acid Motifs / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D015209:Cholangitis, Sclerosing / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006684:HLA-DR Antigens / Q000737:chemistry* / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D055672:Static Electricity; D055815:Young Adult
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains