Biology subjects

Florez-Vargas, O.

Publications and source records attributed to Florez-Vargas, O..

5 recordsLinked to original sources

bioRxiv2020

IFN-{lambda}4 may contribute to HCV persistence by increasing ER stress and enhancing IRF1 signaling

Chronic hepatitis C virus (HCV) infection and cirrhosis are major risk factors for developing hepatocellular carcinoma (HCC). Genetic polymorphisms in the IFNL3/IFNL4 locus have been associated both with impaired clearance of HCV and protection from liver fibrosis, an early stage of cirrhosis. Here, we aimed to address the genetic and functional relationships between IFNL3/IFNL4 polymorphisms, HCV-related cirrhosis, and HCC risk. We evaluated associations between IFNL4 genotype, defined as the presence of rs368234815-dG or rs12979860-T alleles, with cirrhosis and HCC risk in patients with chronic HCV - 2,931 from Taiwan and 3,566 from Japan. We detected associations between IFNL4 genotype and decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwan), but increased risk of HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058, in Japan). In-vitro, IFN-{lambda}4 expression increased ER stress, and enhanced positive regulation of IFN responses via IRF1 induction, which mediated antiproliferative effects in hepatic cells. Our data present novel IFN-{lambda}4-associated pathways that may be contributing to HCV persistence and development of HCC.

cancer biology↗

bioRxiv2020

Isoform-specific characterization implicates alternative splicing in APOBEC3B as a mechanism restricting APOBEC-mediated mutagenesis

APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis, but the understanding of the regulation of their mutagenic activity remains limited. Here, we showed that mutagenic and non-mutagenic A3A and A3B enzymes are produced by canonical and alternatively spliced A3A and A3B isoforms, respectively. Notably, increased expression of the canonical A3B isoform, which encodes the mutagenic A3B enzyme, predicted shorter progression-free survival of bladder cancer patients. Expression of the mutagenic A3B isoform was reduced by exon 5 skipping, generating a non-mutagenic A3B isoform. The exon 5 skipping, which was dependent on the interaction between SF3B1 splicing factor and weak branch point sites in intron 4, could be enhanced by an SF3B1 inhibitor, decreasing the production of the mutagenic A3B enzyme. Thus, our results underscore the role of A3B, especially in bladder cancer, and implicate alternative splicing of A3B as a mechanism and therapeutic target to restrict APOBEC-mediated mutagenesis.

genomics↗

bioRxiv2020

Interferons and viruses induce a novel primate-specific isoform dACE2 and not the SARS-CoV-2 receptor ACE2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, primate-specific isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In vitro, dACE2, which lacks 356 N-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results reconcile current knowledge on ACE2 expression and suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, inflammatory tumor microenvironment, or viral co-infections is unlikely to affect the cellular entry of SARS-CoV-2 and promote infection.

genetics↗

bioRxiv2020

IFN-{lambda}4 increases the risk of gastrointestinal infections and malaria in Malian children

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we analyzed episodes of malaria, gastrointestinal and respiratory infections using information for 30,626 clinic visits from birth through up to 5 years of follow-up. Genetic polymorphisms IFNL4-rs368234815 and IFNL3-rs4803217 that functionally affect type III interferons were genotyped with TaqMan assays. For both genetic variants and each infection, we evaluated time-to-first episode and calculated odds ratios (ORs) for the risk of an infection episode during follow-up, controlling for relevant covariates. Compared to children with the rs368234815-TT/TT genotype (IFN-{lambda}4-Null), each copy of the rs368234815-dG allele was associated with an earlier first episode of a gastrointestinal infection (p=0.003) and respiratory infection (p=0.045). The risk of experiencing an infection episode during the follow-up was also significantly increased with each copy of the rs368234815-dG allele - for gastrointestinal infections (OR=1.53, 95%CI (1.13-2.07), p=0.005) and malaria (OR=1.30, 95%CI (1.02-1.65), p=0.033). IFNL4-rs368234815 and IFNL3-rs4803217 were in moderate linkage disequilibrium in this population (r2=0.78), and all the associations for rs4803217 were weaker and lost significance after adjusting for rs368234815, implicating IFN-{lambda}4 and not IFN-{lambda}3 as the primary cause of these associations. We conclude that the ability to produce IFN-{lambda}4 may have broad health-related implications by negatively affecting the immune response and clinical outcomes of several common infections.

genetics↗

bioRxiv2019

High prevalence of precocious menarche in Puerto Barrios, Guatemala

BackgroundAge of menarche is variable between women with a median age of 14 years old worldwide, and averages ranging from 12-13 years old in developed countries to 15-16 years old in low and middle-income countries. Precocious menarche, occurring before age 11, is rare, with a prevalence of 1.4 to 2.3% in most worldwide populations. Precocious menarche is poorly understood but is associated with early puberty and is a risk factor for pre-teen birth. In studying HPV prevalence in Latin America, we identified a community with a very high rate of precocious menarche. Objective(s)Describe the patterns of precocious menarche in Guatemala. Study DesignReproductive histories were collected from 3385 cancer-free women at the time of routine Pap smear from 4 sites in Guatemala including hospitals in Guatemala City and Puerto Barrios, Izabal. Statistical analyses included determination of the age-specific prevalence of menarche and linear regression to determine the effect of year of birth, study site, number of births and miscarriages, on the age at menarche. ResultsCompared with a low prevalence of precocious menarche observed in Guatemala City (3.1%, 88/2834), we observed a high prevalence of precocious menarche in the city of Puerto Barrios, Izabal, Guatemala (88%, 486/551). We observed a high prevalence of precocious menarche in Puerto Barrios across all age groups. In contrast in Guatemala City, the median age at menarche declined from the age of 14 in 50-60-year-old women to 13 in women under 40 years of age. Hospital records show that the occurrence of both miscarriage and pregnancy under age 14 is substantially higher in Izabal. In addition, the main public hospital in Puerto Barrios accounts for a high fraction of the early pregnancies and miscarriages seen in Guatemala. ConclusionsIn Puerto Barrios, Izabal, Guatemala, the prevalence of menarche before age 11 is dramatically elevated compared to Guatemala City and substantially higher than other worldwide populations. We observed precocious menarche in Puerto Barrios in all age groups examined, indicating that this condition has been common for decades. This finding is supported by the comparatively higher occurrence of early pregnancy and miscarriage in Puerto Barrios compared with Guatemala City. The cause is unknown, but precocious menarche is associated with adverse reproductive outcome in young women and warrants further investigation.

epidemiology↗