Association of killer cell immunoglobulin-like receptor polymorphisms with chronic hepatitis C and responses to therapy in Brazil

Abstract

Soroprevalence for Hepatitis C virus is reported as 2.12% in Northern Brazil, with about 50% of the patients exhibiting a sustained virological response (SVR). Aiming to associate polymorphisms in Killer Cell Immunoglobulin-like Receptors (KIR) with chronic hepatitis C and therapy responses we investigated 125 chronic patients and 345 controls. Additionally, 48 ancestry markers were genotyped to control for population stratification. The frequency of the KIR2DL2 and KIR2DL2+HLA-CAsp80 gene and ligand was higher in chronic infected patients than in controls (p < 0.0009, OR = 3.4; p = 0.001, OR = 3.45). In fact, KIR2DL3 is a weaker inhibitor of NK activity than KIR2DL2, which could explain the association of KIR2DL2 with chronic infection. Moreover, KIR2DS2 and KIR2DS2+HLA-CAsp80 (p < 0.0001, OR = 2.51; p = 0.0084, OR = 2.62) and KIR2DS3 (p < 0.0001; OR = 2.57) were associated with chronic infection, independently from KIR2DL2. No differences in ancestry composition were observed between control and patients, even with respect to therapy response groups. The allelic profile KIR2DL2/KIR2DS2/KIR2DS3 was associated with the chronic hepatitis C (p < 0.0001; OR = 3). Furthermore, the patients also showed a higher mean number of activating genes and a lower frequency of the homozygous AA profile, which is likely secondary to the association with non-AA and/or activating genes. In addition, the KIR2DS5 allele was associated with SVR (p = 0.0261; OR = 0.184).The ancestry analysis of samples ruled out any effects of population substructuring and did not evidence interethnic differences in therapy response, as suggested in previous studies.

Contribution of genes for killer cell immunoglobulin-like receptors (KIR) to the susceptibility to chronic hepatitis C virus infection and to viremia

“…The higher representation of KIR2DS2 and KIR2DL2 genes among our chronically HCV-infected male patients than in healthy controls is in keeping with the favorable effect of the KIR2DL3/KIR2DL3+ C1C1 genotype on the elimination of the virus [13][14][15], because KIR2DS2/KIR2DL2 and KIR2DL3 are mutually exclusive in the centromeric part of the KIR locus [8]. It is also in accord with data published recently by de Vasconcelos et al [28] who observed an association of KIR2DL2 and KIR2DS2 with chronic HCV infection, but they did not give the proportion of males and females in their sample. Interestingly, a ÀKIR2DS2/KIR2DL2À C1C1 (but not KIR2DS2/KIR2DL2 alone) genotype has been recently described as a risk factor for an earlier age at onset of hepatocellular carcinoma in hepatitis B virus infection in Chinese, but, again, There was no statistically significant difference between studied groups (p = 0.8851).…”

“…In the latter study, the co-distribution of KIR2DS3 and KIR2DS5 was not tested; their data are, however, somewhat contradictory to ours, where the presence of KIR2DS3 rather than KIR2DS5 favored a lower viremia in infected individuals. The association of KIR2DS3 (alone and together with KIR2DL2 and KIR2DS2) with chronic hepatitis C was also described recently by de Vasconcelos et al [28]. In HCV-related hepatocellular carcinoma the presence of KIR2DS5 gene was associated with markedly longer overall survival [32].…”

NK cells: tuned by peptide?

“…Additionally, there was loss of the KIR2DS3 allele. This allele has been found to be associated with chronicity for both hepatitis B and hepatitis C and is also a susceptibility factor for Ebola virus . Furthermore, it was absent from the majority of KIR haplotypes identified in other Amerinidian tribes studied, which have haplotypes containing KIR2DS5 rather than KIR2DS3 .…”

Innate and adaptive genetic pathways in HCV infection

“…Therefore the mechanism underlying this association may be complex. The absence of a KIR2DL3:group 1 HLA‐C interaction appears to be detrimental to HCV outcome in a number of different populations .…”