RESUMO
Intravenous drug use has become the principal route of hepatitis C virus (HCV) transmission due to the sharing of infected needles. In this study, we analyzed the distribution of HLA-KIR genotypes among 160 Puerto Rican intravenous drug users (IDUs) with HCV infection and 92 HCV-negative Puerto Rican IDUs. We found a significant association between the presence of different combinations of KIR inhibitory receptor genes (KIR2DL2 and/or KIR2DL3, pC=0.01, OR=0.07; KIR2DL2 and/or KIR2DL3+KIR2DS4, pC=0.01, OR=0.39) and HLA-C1 homozygous genotypes (HLA-C1+KIR2DS4, pC=0.02, OR=0.43; HLA-C1+KIR2DL2+KIR2DS4, pC=0.02, OR=0.40) together with the activating receptor KIR2DS4 (HLA-C1+KIR2DS4+KIR2DL3 and/or KIR2DL2, pC=0.004, OR=0.38) with protection from HCV infection. Our findings in HCV-infected and non-infected IDUs suggest an important role for KIRs (KIR2DL2 and KIR2DL3) with group HLA-C1 molecules, in the presence of activating KIR2DS4, in protection from HCV infection. These results support the hypothesis that activator signaling, mediated by KIR2DS4, plays a determinant role in the regulation of NK cell antiviral-activity.
Assuntos
Antígenos HLA/genética , Hepatite C/genética , Receptores KIR/genética , Abuso de Substâncias por Via Intravenosa/genética , Análise por Conglomerados , Frequência do Gene , Genótipo , Antígenos HLA-C/genética , Hepatite C/virologia , Humanos , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Abuso de Substâncias por Via Intravenosa/virologiaRESUMO
We analyzed the natural killer cell immunoglobulin-like receptor (KIR) genes and immunoglobulin allotypes in the development of type 2 diabetes (T2D) based on body mass index (BMI) measurements (obese vs. non-obese) in Puerto Rican Americans. Genetic interactions between the KIR haplotype A homozygotes (HAH) and its fraction containing two inhibitory receptors 2DL3 and 2DL1 and the activating receptor 2DS4 with immunoglobulin allotypes were studied. We found a significant association between the HAH and T2D (p=0.002; OR=7.97) and its interaction with the immunoglobulin allotype z: GM f/f (-) (p=<0.0001; OR, not determined) only in non-obese individuals. This association were due to the interactions between the 2DL3/2DL3, 2DL1/2DL1, and 2DS4 fragment with GM f/f (-) in T2D patients (p=0.0017; OR=3.45). Analysis based on BMI demonstrated associations in both obese (p=0.037; OR=2.43; 95% CI=0.97-6.31) and non-obese individuals (p=<0.0001; OR=8.38; 95% CI=2.49-29.31). By contrast, the interaction of the GM allotype f/f (-) with the HAH fragment was associated with T2D only in non-obese individuals (p=<0.0001; OR=18.2; 95% CI=3.71-113.4). As expected, interaction of both HAH and its fragment with HLA-C group's ligands were significant. We used informative short tandem repeats (STRs) that distinguish major populations to determine genetic admixture and found that there was no genetic stratification in our cohort. Our findings are consistent with the possibility of an autoimmune and/or innateimmune component in the pathogenesis of T2D: NK receptors with chronic inflammation in obese and genetic interactions with G1M allotype in T2D non-obese possibly mediating autoimmunity.