Evaluation of natural killer cell receptor variation as genetic risk factor for the development of advanced fibrosis and increased liver stiffness in patients with chronic liver disease

Introduction: Recently the natural killer cell receptor G2D (NKG2D) has been shown to be involved in NK-cell induced apoptosis of hepatic stellate cells in chronic hepatitis C virus (HCV) infection. Because stellate cells also play a critical role in liver fibrosis development we speculate that functional polymorphisms in this gene influence fibrosis progression. Thus we studied the influence of a common NKG2D polymorphism that has also been associated to cholangiocarcinoma on liver stiffness, as determined by vibration controlled transient elastography (VCTE).

Patients and methods: Patients with chronic liver disease were recruited, and all patients received VCTE and/or a liver biopsy for the assessment of liver stiffness or fibrosis stage. All patients were genotyped for the single nucleotide polymorphism rs2617167. Association testing was performed using Chi-square statistics for allelic discrimination and Armitage's trend test for associations with genotypes. In addition, we also tested whether the subgroup of patients with chronic HCV infection shows an association with liver stiffness.

Results: A total of 691 patients with chronic liver disease and Caucasian descent were included in the study. The majority of patients were men (60%) and suffered from HCV infection (N = 433, 63%). Patients were subdivided in different TE classes (55%: < 7.5 kPa; 23%: 7.5 – 13 kPa; 22%: > 13 kPa, indicating presence of cirrhosis). Liver stiffness did neither correlate with alleles nor with genotypes (P > 0.05). To exclude that the SNP is relevant in early but not in late-stage liver disease progression, we also tested whether rs2617167 was associated with liver stiffness within classes but no association with stiffness was detected. Liver histology was not associated with liver fibrosis stage either. Albeit the relevance of NKG2D has been shown for HCV infected patients, this subgroup of HCV patients did not show an association.

Conclusions: This elastography-based genetic study indicates that it is unlikely that common genetic variation in the NKG2D gene has an impact on the progression of chronic HCV infection. NKG2D variation does not represent a major risk factor for increased liver stiffness in general or liver fibrosis stages in particular.