Particular genetic variants of ligands for natural killer cell receptors may contribute to the HLA associated risk of primary sclerosing cholangitis.
OBJECTIVE
Combinations of killer immunoglobulin-like receptors (KIRs) and HLA class I ligands that reduce natural killer (NK) cell inhibition have been shown to increase risk for autoimmune diseases. We aimed to clarify to what extent such combinations influence susceptibility to primary sclerosing cholangitis (PSC).


METHODS
Three hundred and sixty-five Scandinavian PSC patients and 368 healthy controls were genotyped for the presence or absence of genes encoding all KIRs using a PCR-SSP approach. KIR binding site variation of HLA-A, -B and -C was also determined.


RESULTS
The KIR gene frequencies were similar among patients and controls. However, the frequency of HLA-Bw4 and -C2, which are ligands for the inhibitory KIRs 3DL1 and 2DL1, respectively, was significantly reduced in PSC patients as compared with controls (38.2% vs. 54.7%, P(corrected)[P(c)]=0.0006 and 42.7% vs. 56.9%, P(c)=0.009, respectively). Two HLA risk haplotypes in PSC (carrying DRB1*0301 or DRB1*1501, respectively) were devoid of both of these alleles, and carried the 5.1 variant of the major histocompatibility complex class I chain-related A (MICA) gene previously reported to influence PSC susceptibility.


CONCLUSIONS
Particular variants of ligands for NK cell receptors encoded at three neighbouring genes in the HLA complex may contribute to PSC associations observed in this genetic region.
Karlsen
Tom H
TH
Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, Oslo, Norway. t.h.karlsen@klinmed.uio.no
Boberg
Kirsten Muri
KM
Olsson
Marita
M
Sun
Ji-Yao
JY
Senitzer
David
D
Bergquist
Annika
A
Schrumpf
Erik
E
Thorsby
Erik
E
Lie
Benedicte A
BA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001327:Autoimmune Diseases; D002648:Child; D015209:Cholangitis, Sclerosing / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D015793:HLA-B7 Antigen / Q000235:genetics; D015795:HLA-B8 Antigen / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D015803:HLA-DR3 Antigen / Q000235:genetics; D015808:HLA-DR6 Antigen / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D008024:Ligands; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009664:Norway; D011110:Polymorphism, Genetic; D011859:Radiography; D011971:Receptors, Immunologic / Q000235:genetics*; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D054341:Receptors, KIR3DL1
D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015793:HLA-B7 Antigen; D015795:HLA-B8 Antigen; C042388:HLA-Bw4 antigen; D015236:HLA-C Antigens; D015803:HLA-DR3 Antigen; D015808:HLA-DR6 Antigen; D059811:HLA-DRB1 Chains; C487961:HLA-DRB1*01:01 antigen; D008024:Ligands; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D054341:Receptors, KIR3DL1