PNPLA3 gene predicts clinical recovery after sustained virological response in decompensated hepatitis C cirrhosis.

BACKGROUND: Patients with decompensated hepatitis C virus (HCV) cirrhosis experience various outcomes after sustained virological response (SVR), ranging from clinical recovery to further deterioration. We hypothesised that the genetic risk for steatosis, namely the polymorphisms rs738409 of Patatin-like Phospholipase Domain-Containing 3 (PNPLA3), rs58542926 of Transmembrane-6-Superfamily-2 (TM6SF2), and rs641738 of Membrane-bound O-acyltransferase Domain-Containing 7 (MBOAT7), is predictive of recovery. METHODS: We prospectively enrolled 56 patients with Child-Pugh (CPT) B/C cirrhosis who underwent antiviral therapy. The primary outcome was change in CPT score at 12, 24, and 48 weeks after SVR. We used a linear mixed-effects model for analysis. RESULTS: Forty-five patients (PNPLA3: 21 CC, 19 CG, 5 GG) survived to the first endpoint without liver transplantation. The mean change in CPT score at 12, 24, and 48 weeks was -1.57 (SE=0.30), -1.76 (SE=0.32), and -2.0 (SE=0.36), respectively, among the patients with the PNPLA3 CC genotype and -0.50 (SE=0.20), -0.41 (SE=0.25), and -0.24 (SE=0.27), respectively, among the other 24 patients. After adjustment for baseline characteristics, the PNPLA3 CG/GG genotypes were associated with a 1.29 (SE=0.30, p<0.0001) point higher CPT score. Most of the difference came from differences in hepatic encephalopathy and bilirubin. The results for rs58542926 and rs641738 were not significant. CONCLUSION: The PNPLA3 CG/GG genotypes could identify a subgroup of patients with decompensated HCV cirrhosis that had suboptimal clinical recovery despite SVR. An understanding of the genetic factors that influence clinical outcomes will help target patients for liver transplant based on individual genetic risk factors and provide insight leading to new therapeutic approaches.

Differences between rat strains in models of retinopathy of prematurity.

PURPOSE: Genetic factors appear to modulate the incidence and severity of retinopathy of prematurity (ROP). Different rat strains may be analogous to genetic differences across human ethnic groups. We investigated the incidence and severity of neovascularization (NV) in Brown Norway (BN) and Sprague Dawley (SD) rats in oxygen-induced retinopathy (OIR) and acidosis-induced retinopathy (AIR) models for ROP. We also studied whether there was a difference in retinal vascular endothelial growth factor (VEGF) mRNA levels in OIR animals. METHODS: Newborn SD and BN rats (110 in both groups) were raised in standardized litters of ten (four OIR, twelve AIR, six non-gavaged room air controls). Beginning on day 1 of life, OIR litters were exposed to seven cycles of hyperoxia (80% O2, 20.5 h) and hypoxia (10% O2, 0.5 h) with a gradual return to 80% O2 over 3 h. This was followed by room air recovery for five days. OIR and OIR control rats were sacrificed on day 13 of life. AIR rats were gavaged twice daily with NH4Cl (10 mmol/kg) from day 2 to day 7 of life, or 15 mmol/kg twice daily on day 2 and then 10 mmol/kg twice daily from day 3 to day 7. AIR and AIR control rats were sacrificed on day 10 or day 13. Retinas from left eyes were dissected, ADPase stained and flatmounted. Presence and severity of NV (clock hours, 0 to 12) was scored by a masked observer. Right retinas from OIR and room air controls were processed for VEGF mRNA analysis. RESULTS: In OIR rats, the incidence of NV was higher in BN than SD rats (100% compared to 5%, p<0.0001). NV was more severe in BN rats (1 to 10 clock hours, median 7 clock hours compared to 0 to 1 clock hours, p=0.0001). In contrast, the incidence of NV in AIR rats was similar in BN and SD rats (4% compared to 0%, p=1.0) in the 10 mmol/kg study, and 18% compared to 0%, (p= 0.15) in the 15 mmol/kg study. Increased levels of retinal VEGF mRNA were found in BN OIR animals when compared to BN room air controls (1.4 fold increase) whereas retinal VEGF mRNA levels were similar between SD OIR and SD room air control animals. CONCLUSIONS: BN rats differ from SD rats in incidence and severity of NV in OIR. The findings in AIR were limited by the low incidence of NV and intolerance to higher multiple doses of NH4Cl. In OIR, the higher severity of NV was associated with higher retinal VEGF mRNA in BN OIR rats. Studies are warranted to investigate the genetic differences between Brown Norway and Sprague Dawley rats in models of ROP. These genetic studies may yield further clues into the pathogenesis of clinical ROP.