POLYMORPHISMS OF α1-ANTITRYPSIN AND INTERLEUKIN-6 GENES AND THE PROGRESSION OF HEPATIC CIRRHOSIS IN PATIENTS WITH A HEPATITIS C VIRUS INFECTION
Motawi T, Shaker OG, Hussein RM, Houssen M
*Corresponding Author: Rasha M. Hussein, Ph.D., Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Salah Salem Street, 62511, Beni-Suef, Egypt. Tel: +20-12-0013-6515. Fax: +20-82-2317-958. E-mail: rasha.hussein@ pharm.bsu.edu.eg
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RESULTS

The Demographic and Biochemical Parameters of the Studied Groups. In this study, we recruited two groups of chronic HCV-infected patients; the chronic hepatic patients and the cirrhotic patients in addition to the control group. We found that the chronic hepatic patients exhibited significantly higher values of ALT, AST and ALP compared with the control group (p <0.05). In the same way, the cirrhotic patient group exhibited significantly higher activities of ALT, AST and ALP in addition to higher values of total bilirubin, prothrombin time and AFP and lower albumin compared to the control group (p <0.05). Interestingly, the cirrhotic patient group exhibited significantly higher values of AST, albumin, prothrombin time, AFP and fibrosis score compared to the chronic hepatic patient group (p <0.05). These results confirm the progression of the end stage complications associated with HCV infection in the cirrhotic patients. The demographic and biochemical parameters of all studied groups are summarized in Table 1. Frequency of Interleukin 6 Genotypes and Alleles of the Studied Groups. The SNP of IL-6 (174 G/C, rs 1800795) was detected in the control, chronic hepatic and cirrhotic patients by the PCR-RFLP method. We found that the G allele was distributed at 100.0% in the control group, while the C allele was found only in the chronic hepatitis and cirrhotic patients at frequencies of 17.6 and 19.2%, respectively (Table 2). In more detail, the IL-6 (GG genotype) showed significantly lower frequency in the cirrhotic patients (61.5%) when compared to the control group (100.0%) at p <0.05. On the other hand, the IL-6 (CC genotype) was only found in the chronic hepatic patients (5.9% frequency), while the heterozygous IL-6 (GC genotype) was detected in both chronic hepatic and cirrhotic patients at 23.5 and 38.5% frequencies, respectively (Table 2). Frequency of α1-Antitrypsin Genotypes and Alleles of the Studied Groups. The S (264 Glu/Val, rs17580) and Z (342 Glu/Lys, rs28929474) mutations of the A1AT gene were detected in the control, chronic hepatic and cirrhotic patients by the PCR-RFLP method. We found that the wild type M allele was the most common allele in all groups. However, the frequency of the M allele decreased significantly in cirrhotic patients (65.4%) when compared to the control group (92.5%). Interestingly, the cirrhotic patients also showed a significantly increased frequency of the S allele (34.6%) compared to the control group (5.0%), while the Z allele was not detected in the cirrhotic patients (Table 3). The distribution of the A1AT genotypes revealed that the A1AT (SS genotype) was only detected in the cirrhotic patients (23.1% frequency) compared to control and chronic hepatic patients (both at 0.0% frequencies). In the same way, the A1AT (ZZ genotype) was only detected in the chronic hepatic patients (11.8% frequency) when compared to control and cirrhotic patients. The heterozygous MS and MZ genotypes were detected mostly in the chronic HCV patients (Table 3). The Biochemical Parameters Associated with Different Interleukin 6 Genotypes. As the low producer, IL-6 (CC genotype), was detected only in the chronic hepatitis patients, comparing the CC genotype with the high producer IL-6 (GG+GC) genotypes in the same group did not show significant increased values of ALT, AST, ALP, total and direct bilirubin or AFP (Table 4). These findings indicate that inheritance of the IL-6 (CC genotype) is not associated with increased risk of developing progressive liver diseases. The Biochemical Parameters Associated with Different α1-Antitrypsin Genotypes. The chronic hepatitis patients with the Z allele (MZ+ZZ genotypes) showed a significantly increased AST activity when compared to the chronic hepatitis patients with either the MM or MS genotypes (p <0.05). Interestingly, the cirrhotic patients with the S allele (MS+SS genotypes) showed significantly increased levels of AST, ALT, total bilirubin, direct bilirubin and lower albumin levels when compared with the cirrhotic liver patients with the A1AT (MM genotype) at p <0.05 (Table 5). These results indicate that inheritance of A1AT (S or Z allele) increases the severity of liver disease in either cirrhotic or chronic hepatitis patients, respectively. Multivariate regression analyses showed that AST (p = 0.003, OR = 1.6, 95% CI = 1.3-2.0) and the S allele of A1AT represented as SS+MS genotypes (p = 0.001, OR = 7.7, 95% CI = 3.4-17.4) to be significantly independent predictors for development of liver cirrhosis. Although the IL-6 gene is known to regulate the expression of acute phase reactants such as A1AT, we did not find a statistically significant correlation between any of the genotypes of IL-6 (GG, GC, CC) and any of the A1AT (MM, MS, MZ, SS, ZZ) genotypes.



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