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Additionally, we applied a recently described test to evaluate the synergistic effects of genetic factors. This demonstrated that the rs12979860-CC genotype and KIR2D元:HLA-C1 homozygosity are protective in isolation ( P.
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This analysis tests whether the combination of the 2 factors provides additional benefit above that due to each factor individually. To determine this, we performed multivariate logistic regression analysis using 3 variables: rs12979860-CC+KIR2D元:HLA-C1 homozygosity rs12979860-CC with or without KIR2D元:HLA-C1 homozygosity and KIR2D元:HLA-C1 homozygosity with or without rs12979860-CC. However, it is not clear whether these 2 protective genetic factors are acting synergistically or independently. In univariate analysis, the frequency of the combination of rs12979860-CC and KIR2D元:HLA-C1 homozygosity in the SR group was 21% as compared with only 7.3% in the chronically infected group ( P =. Similarly, we found an under-representation of rs12979860-CC in EU as compared with SR in both the KIR2D元:HLA-C1 homozygous and nonhomozygous subgroups ( P =. Likewise, the protective effect of KIR2D元:HLA-C1 homozygosity was similar in individuals with the rs12979860-CC genotype (30.6% vs 16.7%, P =. 18 OR, 2.23, 95% CI: 0.73–6.84), most likely because of the small sample size.
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The effect was similar in individuals who were KIR2D元:HLA-C1 homozygous, but this did not reach statistical significance (73.1% vs 54.8%, respectively, P =. In individuals who had spontaneously resolved infection and were not KIR2D元:HLA-C1 homozygous, the frequency of the rs12979860-CC genotype was significantly higher compared with chronically infected individuals (68.3% vs 41.9%, P =. Thus, the rs12979860 polymorphism distinguishes the EU population from those that spontaneously resolve HCV infection. These observations remained similar if only Caucasian individuals were considered ( Supplementary Table 3). This is despite the overall T allele frequency being similar between EU and chronically infected individuals (36.5% vs 32.1%, respectively) ( Supplementary Table 1, Supplementary Table 2). Additionally, we found that there was a trend toward an increase in TT homozygosity in the EU population as compared with both SR (14.9% vs 5.6%, respectively, P =. 019 OR, 2.32, 95% CI: 1.19–4.52), and this genotype was lower in the SR population as compared with the chronically infected individuals (24.7% vs 48.7%, respectively, P <. We also found that CT heterozygosity was more prevalent in the EU as compared with the SR population (43.2% vs 24.7%, respectively, P =. Consistent with previous work, the frequency of the IL28B.rs12979860-CC genotype was significantly higher in the spontaneous resolving population compared with those with chronic infection (69.7% vs 43.6%, respectively, P <. 0005 OR, 0.31 95% confidence interval : 0.16–0.60) but was similar to that found in the 234 individuals with chronic HCV infection (41.9% vs 43.6%, respectively) ( Table 1). The frequency of the protective CC genotype at the SNP rs12979860-CC in the 74 EU individuals was significantly lower than in the 89 SR (41.9% vs 69.7%, respectively, P =. Killer Cell Immunoglobulin-Like ReceptorĪbbreviations used in this paper: EU ( exposed but uninfected), HCV ( hepatitis C virus), Hencore ( Hepatitis C European Network for Cooperative Research collaboration), HLA ( human leukocyte antigen), HLA-C1 ( group 1 HLA-C allotype), IDU ( injection drug users), IFN ( interferon), KIR ( killer cell immunoglobulin-like receptor), NK ( natural killer cells), SNP ( single nucleotide polymorphism), SR ( spontaneous resolvers).Distinct, nonsynergistic innate immune mechanisms can determine outcomes of HCV exposure. Uninfected individuals are therefore a distinct population from patients who spontaneously resolve HCV infection. Resistance to HCV infection in exposed uninfected cases is associated with homozygosity for KIR2D元:HLA-C1 but not the single nucleotide polymorphism IL28B.rs12979860. IL28B and KIR2D元:HLA-C1 are independently associated with spontaneous resolution of viremia following HCV exposure.