Cholangiocarcinoma in primary sclerosing cholangitis is... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms

Melum, Espen1,2; Karlsen, Tom H.1,2*; Schrumpf, Erik1; Bergquist, Annika3; Thorsby, Erik2,4; Boberg, Kirsten M.1; Lie, Benedicte A.2

1 Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway

2 Institute of Immunology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway

3 Department of Gastroenterology and Hepatology, Karolinska University Hospital, Huddinge, Stockholm, Sweden

4 Institute of Immunology, Faculty Division Rikshospitalet, University of Oslo, Oslo, Norway

*Address reprint requests to: Medical Department, Rikshospitalet-Radiumhospitalet Medical Center, Sognsvannsvn 20, 0027 Oslo, Norway

Email:[email protected]

Received 14 May 2007; Accepted 6 August 2007

Published online in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: Southern Norway Regional Health Authority; Grant sponsor: Henrik Homan Fund; Grant sponsor: Anders Jahre Fund; Grant sponsor: Norwegian Foundation for Health and Rehabilitation; Grant sponsor: Norwegian Society for Gastroenterology.

Potential conflict of interest: Nothing to report.

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Abstract

Primary sclerosing cholangitis (PSC) is often complicated by the development of cholangiocarcinoma (CCA). Genetic variation of natural killer cell receptor G2D (NKG2D) has been associated with cancer susceptibility. An important ligand for NKG2D, major histocompatibility complex class I chain-related molecule A (MICA), serves as a marker of cellular stress. The 5.1 allele of the gene encoding MICA has been associated with PSC. In this study, we aimed to investigate the influence of genetic variations in the NKG2D-MICA receptor-ligand pair on the risk of CCA in patients with PSC. Seven single nucleotide polymorphisms (SNPs) covering the NKG2D gene were genotyped in 365 Scandinavian PSC patients and 368 healthy controls with TaqMan technology. Genotype data on the MICA 5.1 variant were available from previous studies. Forty-nine of the PSC patients (13.6%) had developed CCA at the time of study. Two of the NKG2D SNPs were associated with an increased risk of CCA: rs11053781 [odds ratio (OR) = 2.08, 95% confidence interval (CI) = 1.31-3.29, corrected P ( P c) = 0.011] and rs2617167 (OR = 2.32, 95% CI = 1.47-3.66, P c = 0.0020). Carriership of the MICA 5.1 allele was associated with resistance against CCA (OR = 0.43, 95% CI = 0.20-0.95, not corrected P = 0.032). Conclusion: Our results show that genetic variants of the NKG2D receptor are associated with development of CCA in PSC patients. This suggests that interaction between NKG2D and MICA is involved in protection against CCA in PSC. Patients who are homozygous for the nonrisk alleles are unlikely to develop CCA; this finding could be helpful in identifying PSC patients with a low CCA risk. (Hepatology 2007.)

Abbreviations: CCA, cholangiocarcinoma; CI, confidence interval; IBD, inflammatory bowel disease; LD, linkage disequilibrium; MICA, major histocompatibility complex class I chain-related molecule A; NK, natural killer; NKC, natural killer cell receptor complex; NKG2D, natural killer cell receptor G2D; OR, odds ratio; Pc, corrected P value; Pnc, not corrected P value; PSC, primary sclerosing cholangitis; sMICA, soluble major histocompatibility complex class I chain-related molecule A; SNP, single nucleotide polymorphism.