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This study aimed to investigate the plasma levels of Gas6 and soluble Axl (sAxl) in patients with chronic hepatitis C virus (HCV) infection with and without type 2 diabetes mellitus (T2DM). The study involved four groups; 50 patients with chronic HCV, 50 patients with T2DM, 50 patients with chronic HCV and T2DM, and 31 age- and sex-matched healthy controls. T2DM was diagnosed according to American Diabetes Association criteria, HCV antibodies were detected by enzyme-linked immunosorbent assays (ELISA) and confirmed by real-time-polymerase chain reaction. Plasma Gas6 and sAxl levels were assayed in all groups by ELISA. Significant low levels of GAS 6 in HCV/T2DM group versus HCV group were detected (7.92 ± 5.18 vs. 16.09 ± 7.36, respectively, p = 0.000), but higher than T2DM and control groups (p ≥ 0.05), although nonsignificant. HCV load was higher in the HCV group than the HCV/T2DM group (1,888,300 ± 5,595,070 vs. 1,417,900 ± 4,066,460 copies/mL, respectively, p = 0.632). Among HCV group, significant positive correlations were detected between Gas6 and sAxl levels with HCV viral load (r = 0.48, p = 0.000 and r = 0.43, p = 0.002, respectively), while among HCV/T2DM group, significant negative correlations were detected (r = −0.29, p = 0.04 and r = −0.34, p = 0.014, respectively). Significant negative correlations were detected between Gas6/sAxl levels and glycated hemoglobin (r = −0.36, p = 0.01 and r = −0.4, p = 0.003, respectively) in T2DM despite the positive correlations detected in HCV/T2DM (r = 0.27, p = 0.053 and r = 0.55, p = 0.000, respectively). In conclusion, Gas6/Axl system in combined HCV/T2DM diseases may affect the pathogenesis and can alter the biomarkers and complications of both diseases in a manner that differs from a solitary disease. [ABSTRACT FROM AUTHOR]

• HCV infection and type 2 diabetes mellitus (T2DM) are two master public health problems with rising complication and mortality rates. • PD-1, CTL4 gene polymorphisms have been found to be associated with susceptibility to chronic hepatitis B infection. • There is an interest in studying their association with HCV infection to predict their role in disease susceptibility and treatment response. • rs10204525 and rs231775 could serve as a valuable predictors of susceptibility to HCV infection and impact of therapy. • The T allele of rs10204525 is associated with more susceptibility to develop chronic HCV with or without DM and non-responding status after treatment. Also, G allele of rs231775 is associated with more susceptibility to develop chronic HCV with or without DM and non-responding status after treatment. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are immune inhibitory factors that provide inhibitory signals to T cells. A case-controlled genetic association study was conducted in478 patients (160 patients with chronic Hepatitis C virus (HCV) and diabetes mellitus (DM) and156 patients with chronic HCV without DM) and162healthy controls. We genotyped selected single nucleotide polymorphisms (SNPs) of rs10204525 and rs231775using real-time-polymerase chain reaction (RT-PCR). Our study revealed thatthers10204525 CT genotype was significantly associated with a high susceptibility to chronic HCV infection and to HCV+DM (adjusted odds ratio (OR)7.531, 95% confidence interval (CI):4.099–13.836, P < 0.0001 and adjusted OR 7.791, 95% CI:4.244–14.303, P < 0.0001, respectively).In addition, the frequency of CT+TT genotypes versus the CC genotype and the T allele versus the C allele were elevated in non-responder patients to antiviral therapy compared with responder patients (P < 0.0001) in HCV group. For rs231775,the AG genotype was significantly associated with a high susceptibility to chronic HCV infection and HCV infection with DM (adjusted OR 5.124,95% CI:3.150–8.334, P < 0.0001 and adjusted OR 20.594, 95% CI:11.026–38.467, P < 0.0001, respectively).Furthermore, the frequency of AG+GG genotypes versus the CC genotype and the G allele versus the A allele was elevated in non-responder patients to antiviral therapy when compared with responder patients in the HCV and HCV+DM groups(P < 0.05). Both rs10204525 and rs231775 are associated with a risk of chronic HCV, with or without DM. [ABSTRACT FROM AUTHOR]