Electrostatic Modifications of the Human Leukocyte Antigen-DR P9 Peptide-Binding Pocket and Susceptibility to Primary Sclerosing Cholangitis
Artikel i vetenskaplig tidskrift, 2011

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 x 10(-32) and P = 1.8 x 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. Conclusion: The results suggest that in patients with PSC, residues 37 and 86 of the HLA-DR beta chain critically influence the electrostatic properties of pocket P9 and thereby the range of peptides presented. (HEPATOLOGY 2011;53:1967-1976)

expression

recognition

class-ii alleles

autoimmune hepatitis

ulcerative-colitis

beta-chain

haplotypes

genome-wide association

resistance

t-cells

Författare

Johannes R Hov

Rikshospitalet-Radiumhospitalet HF

Oslo University Hospital

Universitetet i Oslo

V. Kosmoliaptsis

University of Cambridge

Addenbrooke's Hospital

James A Traherne

Cambridge Institute for Medical Research

Marita Olsson

Chalmers, Matematiska vetenskaper, matematisk statistik

Göteborgs universitet

Kirsten Muri Boberg

Rikshospitalet-Radiumhospitalet HF

Annika Bergquist

Karolinska universitetssjukhuset

Erik Schrumpf

Universitetet i Oslo

Rikshospitalet-Radiumhospitalet HF

J. A. Bradley

University of Cambridge

C. J. Taylor

Addenbrooke's Hospital

Benedicte Alexandra Lie

Oslo University Hospital

J. Trowsdale

Cambridge Institute for Medical Research

Tom H Karlsen

Rikshospitalet-Radiumhospitalet HF

Hepatology

0270-9139 (ISSN) 1527-3350 (eISSN)

Vol. 53 1967-1976

Ämneskategorier

Biologiska vetenskaper

DOI

10.1002/hep.24299