L. Rojas

Insulin resistance predicts sustained virological response to treatment of chronic hepatitis C independently of the IL28b rs12979860 polymorphism

Insulin resistance has been strongly associated with the attainment of sustained viral response (SVR) in hepatitis C patients.

The Hepatitis C Virus Modulates Insulin Signaling Pathway In Vitro Promoting Insulin Resistance

Insulin is critical for controlling energy functions including glucose and lipid metabolism. Insulin resistance seems to interact with hepatitis C promoting fibrosis progression and impairing sustained virological response to peginterferon and ribavirin. The main aim was to elucidate the direct effect of hepatitis C virus (HCV) infection on insulin signaling both in vitro analyzing gene expression and protein abundance. Huh7.5 cells and JFH-1 viral particles were used for in vitro studies. Experiments were conducted by triplicate in control cells and infected cells. Genes and proteins involved in insulin signaling pathway were modified by HCV infection. Moreover, metformin treatment increased gene expression of PI3K, IRS1, MAP3K, AKT and PTEN more than >1.5 fold. PTP1B, encoding a tyrosin phosphatase, was found highly induced (>3 fold) in infected cells treated with metformin. However, PTP1B protein expression was reduced in metformin treated cells after JFH1 infection. Other proteins related to insulin pathway like Akt, PTEN and phosphorylated MTOR were also found down-regulated. Viral replication was inhibited in vitro by metformin. A strong effect of HCV infection on insulin pathway-related gene and protein expression was found in vitro. These results could lead to the identification of new therapeutic targets in HCV infection and its co-morbidities.

Epibiotic Diatoms Are Universally Present on All Sea Turtle Species

The macro-epibiotic communities of sea turtles have been subject to growing interest in recent years, yet their micro-epibiotic counterparts are almost entirely unknown. Here, we provide the first evidence that diatoms are epibionts for all seven extant species of sea turtle. Using Scanning Electron Microscopy, we inspected superficial carapace or skin samples from a single representative of each turtle species. We distinguished 18 diatom taxa from these seven individuals, with each sea turtle species hosting at least two diatom taxa. We recommend that future research is undertaken to confirm whether diatom communities vary between sea turtle species and whether these diatom taxa are facultative or obligate commensals.

Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection

Host–viral genetic interaction has a key role in hepatitis C infection (HCV) and maybe in the viral selection. In a preliminary GWAS analysis, we identified BTN3A2 rs9104 to be associated with HCV genotype 1. Therefore, our aim was to determine the influence of BTN family on the selection of HCV genotype. We performed a fine-mapping analysis of BTN gene region in a cohort of chronic HCV infection (N=841), validating significant results in another independent chronic HCV infection cohort (N=637), according to selection of viral genotype. BTN3A2 rs9104, BTN3A2 rs733528, BTN2A1 rs6929846, BTN2A1 rs7763910 and BTN3A3 rs13220495 were associated with viral genotype selection. Interestingly, BTN3A2 rs9104 GG genotype was closely related to genotype 1 infection (80.7% (394/488) compared with genotype 3 infection (53.5% (23/43); P=0.0001) in patients harboring IL28B-CT/TT genotype, although this effect was not observed in IL28B-CC genotype. Similarly, BTN3A3 rs13220495 CC genotype was linked to genotype 3 infection (100% (32/32)) compared to genotype 1 (87.3% (137/157); P=0.028) in patients harboring IL28B-CC genotype, but did not in IL28B-CT/TT genotype. Genetic variants in the butyrophilin family genes may alter susceptibility to infection, selecting HCV genotype and influencing disease progression. BTN3A2 rs9104 was strongly associated with genotype 1 infection and the haplotype BTN3A3 rs13220495 CC+IL28B genotype CC was universal in patients with hepatitis C genotype 3a.

Role of ITPA and SLC28A2 genes in the prediction of anaemia associated with protease inhibitor plus ribavirin and peginterferon in hepatitis C treatment

BACKGROUND Anaemia is a common side-effect of ribavirin (RBV) use that overwhelms management of hepatitis C when protease inhibitors are added. AIM To assess the pharmacogenomic impact of candidate genes SLC28A2, SLC28A3 and ITPA on anaemia in patients receiving triple therapy. METHODS Patients (n=161) with chronic hepatitis C genotype 1 treated with telaprevir (n=95) or boceprevir (n=66) were included. Using RT-PCR we genotyped ITPA (rs1127354, rs7270101) and SLC28A3 (rs56350726, rs10868138) and SLC28A2 (rs11854484). Clinically significant anaemia (CSA) was diagnosed when at least one of the following criteria was observed: (a) haemoglobin <8.5g/dL during treatment; (b) blood transfusion required; (c) erythropoietin administered. RESULTS CSA occurred in 44% (69/157) of patients and was associated with SLC28A2 rs11854484 [CC/CT genotypes: 33% (26/78) vs. TT genotype: 56% (36/64); p=0.006]. Further, the needed for blood transfusion was related to genotype [CC: 0% (0/18) vs. CT: 13% (8/61) vs. TT: 27% (17/64); p=0.016]. Similarly, ITPA rs1127354 genotypes [AA/AC: 19% (3/16) vs. CC: 45% (61/135; p=0.060] were linked to CSA. In multivariate analysis, SLC28A2 rs11854484 TT genotype (OR:2.33;95%CI:1.10-4.95; p=0.027), female sex (OR:2.54;95% CI:1.13-5.71;p=0.024) and Hb drop at week 4) OR: 1.36; 95CI%: 1.11-1.67; p=0.003) were independently associated with CSA. Similarly, ITPA rs1127354 genotypes [AA/AC: 16% (3/19) vs. CC: 63% (85/134); p=0.0001] and ITPA rs6051702 genotypes [CC/CA: 46% (26/57) vs. CC: 65% (60/93); p=0.023] were related to Hb drop of >3g/dL at week 4. CONCLUSIONS In patients receiving first generation protease inhibitors, genotype SLC28A2 rs11854484 predicts CSA, and helps to identify a subgroup of patients with better tolerance of triple therapy.