PMID- 21413052
OWN - NLM
STAT- MEDLINE
DCOM- 20110829
LR  - 20220129
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 53
IP  - 6
DP  - 2011 Jun
TI  - Electrostatic modifications of the human leukocyte antigen-DR P9 peptide-binding 
      pocket and susceptibility to primary sclerosing cholangitis.
PG  - 1967-76
LID - 10.1002/hep.24299 [doi]
AB  - 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-DRbeta chain critically 
      influence the electrostatic properties of pocket P9 and thereby the range of 
      peptides presented.
CI  - Copyright (c) 2011 American Association for the Study of Liver Diseases.
FAU - Hov, Johannes R
AU  - Hov JR
AD  - Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo 
      University Hospital Rikshospitalet, Oslo, Norway.
FAU - Kosmoliaptsis, Vasilis
AU  - Kosmoliaptsis V
FAU - Traherne, James A
AU  - Traherne JA
FAU - Olsson, Marita
AU  - Olsson M
FAU - Boberg, Kirsten M
AU  - Boberg KM
FAU - Bergquist, Annika
AU  - Bergquist A
FAU - Schrumpf, Erik
AU  - Schrumpf E
FAU - Bradley, J Andrew
AU  - Bradley JA
FAU - Taylor, Craig J
AU  - Taylor CJ
FAU - Lie, Benedicte A
AU  - Lie BA
FAU - Trowsdale, John
AU  - Trowsdale J
FAU - Karlsen, Tom H
AU  - Karlsen TH
LA  - eng
GR  - G0401569/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110513
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
SB  - IM
CIN - Hepatology. 2011 Jun;53(6):1798-800. PMID: 21538433
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Amino Acid Motifs/genetics
MH  - Binding Sites/genetics
MH  - Case-Control Studies
MH  - Child
MH  - Cholangitis, Sclerosing/epidemiology/genetics
MH  - Female
MH  - Genetic Predisposition to Disease/*genetics
MH  - Genotype
MH  - HLA-DR Antigens/*chemistry/*genetics
MH  - HLA-DRB1 Chains
MH  - Haplotypes/genetics
MH  - Humans
MH  - Logistic Models
MH  - Male
MH  - Middle Aged
MH  - Risk Factors
MH  - *Static Electricity
MH  - Young Adult
PMC - PMC3128712
EDAT- 2011/03/18 06:00
MHDA- 2011/08/30 06:00
CRDT- 2011/03/18 06:00
PHST- 2010/03/07 00:00 [accepted]
PHST- 2010/11/23 00:00 [received]
PHST- 2011/03/18 06:00 [entrez]
PHST- 2011/03/18 06:00 [pubmed]
PHST- 2011/08/30 06:00 [medline]
AID - 10.1002/hep.24299 [doi]
PST - ppublish
SO  - Hepatology. 2011 Jun;53(6):1967-76. doi: 10.1002/hep.24299. Epub 2011 May 13.