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.