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In the present case–control study, a total of 592 volunteers were enrolled, among these 292 individuals with persistent HCV infection including 92 patients with mild chronic hepatitis C and 200 with advanced liver disease (AdLD) including liver cirrhosis and hepatocellular carcinoma. In addition, 100 subjects who spontaneously cleared HCV and 200 healthy controls were recruited. The demographic, biochemical, viral characteristics of the study population are shown in Table 1.
Healthy controls (n = 200) Chronic HCV infection (n = 292) HCV-spontaneous clearance (n = 100) Age (years) 55 [13-93] 63 [20-88] 58 [20-76] Gender (%) Male 67 (33.5) 108 (36) 41(41) Female 133 (66.5) 192 (64) 59 (59) Biochemical variables (mean ± SD) Alanine aminotransferase (IU/L) 35.33 ± 21.52 78.43 ± 55.23 46.44 ± 56.25 Aspartate aminotransferase (IU/L) 29.35 ± 16.39 68.85 ± 46.25 34.7 ± 21.43 Bilirubin (μmol/L) NA 15.19 ± 6.08 15.16 ± 11.17 Creatinine (μmol/L) NA 108.54 ± 199.72 82.34 ± 34.55 Fasting serum glucose (g/L) 0.95 ± 0.19 1.06 ± 0.41 1.23 ± 0.54 Total cholesterol (g/L) 1.91 ± 0.38 1.53 ± 0.36 1.72 ± 0.38 Triglycerides (g/L) 1.31 ± 0.68 1.04 ± 0.37 1.37 ± 1.33 HDL-cholesterol (g/L) 0.54 ± 0.36 0.52 ± 0.17 0.48 ± 0.10 LDL-cholesterol (g/L) 1.11 ± 0.38 0.86 ± 0.6 0.94 ± 0.36 Median viral load (IU/mL) NA 2.8 E + 06 - [range] [0.9 E + 03 - 64.5 E + 06] Viral genotypes (%) Genotype 1 - 59.90 - Genotype 2 - 39.06 - Genotype 3 - 0.52 - Genotype 4 - 0.52 - Disease stages (n) mCHC - 92 - AdLD - 127 - HCC - 73 - SD standard deviation, Na non applicable, HDL high density lipoprotein, LDL low density lipoprotein, mCHC mild chronic hepatitis C, AdLD advanced liver disease, HCC hepatocellular carcinoma. Table 1. Baseline characteristics of healthy subjects, chronic HCV patients and HCV-spontaneous clearance group.
Patients with advanced liver fibrosis were older (P < 0.0001) than the others. Serum aminotransferases and bilirubin levels were very significantly increased in the AdLD group as compared to the mCHC group (P < 0.0001). Moreover, AdLD patients exhibited significantly higher values of fasting serum glucose (P= 0.003) but lower total cholesterol and LDL-cholesterol values compared to the mCHC group (P < 0.05). No significant difference was observed regarding creatinine, triglyceride, HDL-cholesterol and HCV viral load between AdLD and mCHC groups (Table 2). An analysis of biological parameters and viral characteristic of patients with CHC infection according to HCV genotypes was also performed. We observed that patients infected with HCV genotype 1 have higher serum triglyceride (P= 0.001) and lower LDL-cholesterol levels (P= 0.01) compared to genotype 2-infected patients. There was no difference regarding fasting serum glucose, total cholesterol and HDL-cholesterol levels between genotypes 1 and 2 (P > 0.05, data not shown). Likewise, serum aminotransferase level was significantly higher in HCV genotype 1-infected group compared to the genotype 2-infected subset (P= 0.01, Data not shown). However, no significant difference between HCV genotypes regarding viral loads was observed (P> 0.05, data not shown). These results confirm that the progression of the liver disease due to HCV includes both features of liver injury and metabolic traits with genotype 1 apparently capable to more profoundly disturb liver function than genotype 2.
Mild chronic hepatitis (n = 92) Advanced liver disease (n = 200) P value Mean age ± SD (years) 57.13 ± 14.09 64.14 ± 9.47 < 0.0001 Gender (%) Male 26 (27.37) 41 (31.30) 0.558 Female 69 (72.63) 90 (68.70) Biochemical variables (mean ± SD) Alanine aminotransferase (IU/L) 53.63 ± 39.77 96.69 ± 58.73 < 0.0001 Aspartate aminotransferase (IU/L) 42.91 ± 24.91 87.94 ± 51.96 < 0.0001 Bilirubin (μmol/L) 13.13 ± 5.54 16.76 ± 6.01 < 0.0001 Creatinine (μmol/L) 87.91 ± 165.39 130.56 ± 249.41 0.148 Fasting serum glucose (g/L) 0.97 ± 0.19 1.14 ± 0.53 0.003 Total cholesterol (g/L) 1.60 ± 0.36 1.47 ± 0.31 0.004 Triglycerides (g/L) 1.03 ± 0.38 1.06 ± 0.40 0.570 HDL-cholesterol (g/L) 0.54 ± 0.19 0.51 ± 0.15 0.186 LDL-cholesterol (g/L) 0.91 ± 0.68 0.74 ± 0.31 0.012 Median viral load (IU/mL) 2.7 E + 06 2.9 E + 06 0.818 [range] [1.7 E + 03-31.8 E + 06] [0.9 E + 03-64.5 E + 06] Viral genotypes (%) Genotype 1 53.85 64.03 0.114 Genotype 2 46.15 34.21 - Genotype 3 - 0.88 - Genotype 4 - 0.88 - SD standard deviation, HDL high density lipoprotein, LDL low density lipoprotein. Table 2. Baseline characteristics of mild and advanced liver diseases groups.
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To estimate the frequencies of the PPARGC1A polymorphisms in Moroccan population, rs8192678 and rs12640088 SNPs were genotyped in 200 healthy controls. The distributions of both SNPs in healthy control group complied with Hardy–Weinberg equilibrium (P> 0.05). The minor allele (A) frequency (MAF) in Moroccan population was 0.175 for rs8192678 and 0.115 for rs12640088, respectively (Table 3).
PPARGC1A Healthy controls n = 200 (%) Spontaneous clearance n = 100 (%) Persistent infection n = 292 (%) Subjects with persistence versus subjects with spontaneous clearance OR (95% Cl) P value rs8192678 G/G 142 (71) 48 (48) 166 (56.85) 1 G/A 46 (23) 44 (44) 105 (35.96) 0.69 [0.43-1.11] 0.126 A/A 12(6) 8 (8) 21 (7.19) 0.76 [0.32-1.82] 0.536 G allele 0.825 ± 0.021 0.700 ± 0.032 0.748 ± 0.018 1 A allele 0.175 ± 0.021 0.300 ± 0.032 0.252 ± 0.018 0.78 [0.55-1.12] 0.181 Dominant model 48/52 166/126 0.70 [0.44-1.10] 0.125 Recessive model 92/8 271/21 1.12 [0.48-2.62] 0.789 rs12640088 A/A 154 (77) 75 (75) 221 (75.68) 1 A/C 46 (23) 22 (22) 64 (21.92) 0.99 [0.57-1.71] 0.963 C/C 0 (0) 3 (3) 7 (2.40) 0.79 [0.20-3.14] 0.739 A allele 0.885 ± 0.015 0.860 ± 0.026 0.866 ± 0.014 1 C allele 0.115 ± 0.015 0.140 ± 0.026 0.134 ± 0.014 0.95 [0.59-1.51] 0.818 Dominant model 75/25 221/71 0.96 [0.57-1.63] 0.890 Recessive model 97/3 285/7 1.26 [0.32-4.97] 0.745 Table 3. Effect of PPARGC1A polymorphisms on the outcomes of HCV infection.
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Outcomes regarding the impact of PPARGC1A variant on spontaneous HCV clearance are displayed in Table 3. Prevalence of homozygous A/A genotype at rs8192678 was 8.0% in the spontaneously recovered group and 7.2% in the HCV persistent group, while homozygous C/C genotype at rs12640088 was 3.0% in the spontaneous recovery group compared to 2.4% in the persistence group. There were no significant differences in the distribution of the genotype frequencies between groups (P> 0.05).
When the rs8192678 G/G and rs12640088 A/A genotypes were used as the reference group, none of the G/A, A/A and A/C, C/C genotypes were associated with chronicity (adjusted ORs = 0.69, 95% CI 0.43–1.11; 0.76, 95% CI 0.32–1.82 and 0.99, 95% CI 0.57–1.71; 0.79, 95% CI 0.20–3.14, respectively). The A/A and C/C genotypes were not associated either with spontaneous resolution of HCV infection.
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In order to analyze the effect of the two polymorphisms on liver disease progression in the Moroccan population, we tested the association of rs8192678 and rs12640088 with fibrosis stage by multiple logistic regression analysis adjusted for age, gender and viral load. CHC patients were stratified according to fibrosis stages as absent/mild (Mild group) or significant (AdLD group). The result indicated that age, male sex, cholesterol, GGT, ALT and AST were associated with advanced fibrosis (P < 0.05). On the other hand, we observed an absence of impact of both rs8192678 AA and rs12640088 CC genotypes on progression of liver disease (OR = 0.71; 95% CI 0.20–2.49; P= 0.739; OR = 1.28; 95% CI 0.25–6.54; P= 0.512, respectively Table 4).
Mild group (n = 92) Advanced group (n = 200) OR 95% CI P value Age (years) 58.5 [51-67] 65 [58-73] 1.06 1.04-1.09 < 0.001 Male sex (%) 23 (25.0%) 81 (41.3%) 2.1 1.23-3.71 0.011 Total cholesterol (g/L) 1.64 [1.36-1.85] 1.42 [1.27-1.68] 0.23 0.07-0.75 0.015 Triglycerides (g/L) 0.96 [0.81-1.27] 0.98 [0.78-1.21] 1.12 0.41-3.06 0.874 HDL (g/L) 0.52 [0.42-0.66] 0.51 [0.38-0.60] 0.14 0.01-1.73 0.232 LDL (g/L) 0.89 [0.60-1.15] 0.80 [0.50-1.00] 0.42 0.10-1.68 0.200 Gamma-glutamyltransferase (IU/L) 27.0 [19.040.0] 63.5 [38.2-119] 1.02 1.01-1.03 < 0.001 ALT (IU/L) 40.5 [28.2-61.8] 82.0 [54.0-123] 1.02 1.01-1.04 < 0.001 AST (IU/L) 33.5 [27.0-44.2] 76.0 [51.5-116] 1.04 1.02-1.06 < 0.001 PPARGC1A rs8192678 AA genotype 4 (4.35%) 8 (6.30%) 0.71 0.20-2.49 0.739 PPARGC1A rs12640088 CC genotype 3 (2.36) 3 (2.36) 1.28 0.25-6.54 0.512 Factors associated with progression of liver disease in chronic hepatitis C patients.
HDL high density lipoprotein, LDL low density lipoprotein, ALT alanine aminotransferase, AST Aspartate aminotransferase, PPARGC1A Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, OR Odds ratio, CI confidence interval.Table 4. Factors associated with disease progression of HCV infection.
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No significant associations were found between rs8192678 and rs12640088 SNPs with biochemical features available (Fig. 1).
Figure 1. Association of rs8192678 and rs12640088 genotypes with lipid profile and blood glucose in CHC patients. Expression of serum cholesterol (A), HDL (B), LDL (C), Triglycerides (D) and Glycemia (E) according to genotypes of PPARGC1A rs8192678. Expression of serum cholesterol (F), HDL (G), LDL (H), Triglycerides (I) and Glycemia (J) according to genotypes of PPARGC1A rs12640088. Data are expressed as the mean and standard deviation. Statistical analyses were performed using Kruskal–Wallis.