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Background The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C ( CHC). Aim To test in genotype 1(G1)- CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis. Methods Four hundred and thirty-four consecutively biopsied Caucasian G1- CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients. Results The prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype ( P = 0.02). By multiple logistic regression, PNPLA3 genotype ( OR 1.54, 95% CI 1.03-2.30, P = 0.03), together with age ( OR 1.03, 95% CI 1.00-1.05, P = 0.02), BMI ≥ 30 ( OR 2.06, 95% CI 1.04-4.10, P = 0.03) and homoeostasis model assessment ( HOMA, OR 1.18, 95% CI 1.04-1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non-obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders ( OR 2.06, 95% CI 1.26-3.36, P = 0.004). We showed an independent association between steatohepatitis ( OR 2.05, 95% CI 1.05-4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA ( P = 0.002). Conclusion In patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non-obese subjects. [ABSTRACT FROM AUTHOR]

Lower 25-hydroxyvitamin D [25( OH) D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients ( G1 CHC). In addition, a recent genome-wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D-binding protein, GC) affecting 25( OH) D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy-proven G1 CHC were consecutively evaluated. The 25( OH) D serum levels were measured by high-pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype ( P = 0.003) and the severity of fibrosis ( P = 0.03) were independent factors associated with lower 25( OH) D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/ TG genotype ( P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age ( OR, 1.056; 95% CI, 1.023-1.089, P = 0.001), low cholesterol ( OR, 0.984; 95% CI, 0.974-0.994, P = 0.002), high triglycerides ( OR, 1.008; 95% CI, 1.002-1.015, P = 0.01), low 25( OH)D ( OR, 0.958; 95% CI, 0.919-0.999, P = 0.04), DHCR7 GG genotype ( OR, 4.222; 95% CI, 1.106-16.120; P = 0.03), moderate-severe steatosis ( OR, 2.588; 95% CI, 1.355-4.943; P = 0.004) and moderate-severe necroinflammatory activity (grading) ( OR, 2.437; 95% CI, 1.307-4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1 CHC, GG homozygosis for DHCR7 gene and lower 25( OH) D levels are independently associated with the severity of liver fibrosis. [ABSTRACT FROM AUTHOR]