Despite decades of concern over the carcinogenic potential of agricultural pesticides, toxicological studies relying on single endpoints have yet to establish a definitive link between environmental pesticide exposure and cancer in real-world contexts. Here we use an integrative spatial Bayesian framework that merges high-resolution environmental pesticide risk modelling with comprehensive cancer registry data to map pesticide-linked cancer clusters in Peru with unprecedented precision. Our process-based model, encompassing 31 key pesticide active ingredients, together with an innovative stratification of cancer cases by developmental lineage, reveals a robust spatial association between environmental pesticide exposure risk and cancer incidence. In pesticide-associated cancer hotspots, exposomic profiling of liver tissue-a primary target of chemical carcinogens-uncovers a distinct transcriptomic signature of pesticide exposure, implicating a non-genotoxic mode of action that disrupts core regulatory circuitries sustaining cell identity. Collectively, these findings strongly support a mechanistic link between pesticide exposure and cancer, challenging assumptions of human non-carcinogenicity derived from reductionist experimental models. This study redefines the exposome as a lineage-conditioned, mechanistically tractable framework and shows how complex pesticide mixtures can contribute to carcinogenic trajectories, with profound and far-reaching implications for global health policy and socio-ecological equity.

In the original publication [...].

Intrahepatic cholangiocarcinoma (ICA) is a highly aggressive primary liver cancer, which originates from the epithelial cells of the bile ducts. The transcriptional profile of metabolic enzymes was investigated at both bulk and single-cell levels in tumor samples from distinct ICA cohorts. In a training cohort (TCGA consortium), 16 genes encoding for metabolic enzymes were found overexpressed in cases with poor survival. A computed metabolic gene expression score was significantly associated with worse ICA prognosis at the univariate level (overall survival [OS] log-rank p = 8.2e-4). After adjusting for Ishak fibrosis score and tumor staging, the metabolic expression remained an independent predictor of poor prognosis (multivariate OS log-rank p = 0.01). Seven genes encoding key enzymes (FH, MAT2B, PLOD2, PLOD1, PDE6D, ALDOC, and NT5DC3) were validated as markers of the proliferative subclass of ICA in the GSE32225 dataset, related to poor prognosis. The metabolic score was significantly different between the inflammatory and proliferative subclasses in the validation cohort (p < 2.2e-16). At the single-cell level, in the tumor microenvironment of 10 ICA patients, these seven enzymes were predominantly expressed by malignant cells. The single-cell metabolic score was thus higher in malignant cells. This study identifies a metabolic transcriptional program linked to poor prognosis in ICA, independent of fibrosis and tumor staging.

In the published publication [...]

Background Restriction factors are host cell proteins that limit virus replication and form part of the intrinsic immune response, acting as a first line of defense. Hepatitis B virus (HBV) does not escape this rule and TREX1, a host restriction enzyme, plays a key role in inhibiting HBV replication.Methods TREX1-expressing constructs were generated and modified by site-directed mutagenesis. The location and activity of these constructs were analyzed by immunofluorescence and fluorescence-activated cell sorting. HepaD38 cells were transfected or transduced with TREX1 constructs with or without cobalt chloride-mimicked hypoxia and HBV replication was quantified by quantitative polymerase chain reaction.Results TREX1 was identified as a restriction factor that suppresses HBV replication. Furthermore, TREX1 expression was enhanced under cobalt chloride-induced hypoxia, leading to a 2-fold reduction in HBV replication. Analysis of 36 HBV-infected patients with hepatocellular carcinoma revealed that TREX1 expression was inversely correlated to the HBV viral load and HBV covalently closed episomal circular DNA (cccDNA).Conclusions Current treatments fail to eliminate HBV genomic reservoirs, which persist as cccDNA. It would be therapeutically relevant to study whether HBV nucleocapsid recycling containing TREX1 enzyme could be released into the nucleus and degrade the viral and nuclear DNA of infected cells. Under cobalt chloride-induced hypoxia, TREX1 was upregulated, enhancing its intrinsic immunity role by inhibiting hepatitis B virus (HBV) replication. Data revealed an inverse correlation between TREX1 expression, HBV viral load, and cccDNA levels in patients, highlighting the critical function of TREX1 in restricting viral replication.

Hepatoblastoma is the most common primary liver cancer in children. Poor outcomes are primarily associated with patients who have distant metastases. Using the Mammalian Metabolic Enzyme Database, we investigated the overexpression of metabolic enzymes in hepatoblastoma tumors compared to noncancerous liver tissue in the GSE131329 transcriptome dataset. For the overexpressed enzymes, we applied ElasticNet machine learning to assess their predictive value for metastasis. A metabolic expression score was then computed from the significant enzymes and integrated into a clinical-biological logistic regression model. Forty-one overexpressed enzymes distinguished hepatoblastoma tumors from noncancerous liver tissues. Eighteen of these enzymes predicted metastasis status with an AUC of 0.90, demonstrating 85.7% sensitivity and 92.3% specificity. ElasticNet machine learning identified DNMT3B and PFKFB4 as key predictors of metastasis. Univariate analyses confirmed the significance of these enzymes, with respective p-values of 0.0058 and 0.0091. A metabolic score based on DNMT3B and PFKFB4 expression discriminated metastasis status and high-risk CHIC scores (p-value = 0.005). The metabolic score was more sensitive than the C1/C2 classifier in predicting metastasis (accuracy: 0.72 vs. 0.55). In a regression model integrating the metabolic score with epidemiological parameters (gender, age at diagnosis, histological type, and clinical PRETEXT stage), the metabolic score was confirmed as an independent adverse predictor of metastasis (p-value = 0.003, odds ratio: 2.12). This study identified the dual overexpression of PFKFB4 and DNMT3B in hepatoblastoma patients at risk of metastasis (high-risk CHIC classification). The combined tumor expression of DNMT3B and PFKFB4 was used to compute a metabolic score, which was validated as an independent predictor of metastatic status in hepatoblastoma.

(1) Background: Hepatoblastoma is the most common primary liver cancer in children. Nowadays, poor outcome occurs essentially for patients with distant metastases; (2) Methods: Starting from Mammalian Metabolic Enzyme Database over expression of metabolic enzymes was searched in hepatoblastoma tumors as compared to noncancerous liver tissue in transcriptome dataset GSE131329. With overexpressed enzymes, Elasticnet machine learning tuning was performed according to metastasis status outcome. With significant enzymes a metabolic expression score was computed and integrated in multivariate clinical-biological logistic model; (3) Results: Forty-one overexpressed enzymes discriminate hepatoblastoma tumors and noncancerous liver tissues. Eighteen of them predict metastasis status (AUC 0.90) with 85.7% of sensibility and 92.3% of specificity. Elasticnet machine learning model tuning highlighted major importance of DNMT3B and PFKFB4 expression to predict metastasis. Role of these two enzymes was confirmed by univariate analyses with respective p-values: 0.0058 and 0.0091. Metabolic score computed with combined expression of DNMT3B and PFKFB4 discriminates metastasis status and high-risk CHIC score by univariate analysis (p-value=0.005). Meta.score was found more sensitive than C1/C2 classifier to predict metastasis status (accuracy: 0.72 versus 0.55). Integration of meta.score (DNMT3B, PFKFB4) with epidemiological parameters: gender, age at diagnosis, histological types, and clinical PRETEXT stages in a multivariate model confirmed independent adverse role of meta.score to predict metastasis status (multivariate p-value=0.003, odds ratio: 2.12); (4) Conclusions: Based on metabolic enzyme expression program of hepatoblastoma, we characterized a dual overexpression of PFKFB4 and DNMT3B in samples of patients at risk of metastasis (High risk CHIC stratification). With combined tumor expression of DNMT3B and PFKFB4 a meta.score was computed and this parameter was confirmed as an independent adverse score to predict metastatic status during hepatoblastoma.

(1) Background: Hepatoblastoma is the most common primary liver malignancy in children. During its development, metabolic reprogramming becomes particularly relevant due to the liver's intrinsic metabolic functions. Enhanced glycolysis, glutaminolysis, and fatty acid synthesis have been implicated in the proliferation and survival of hepatoblastoma cells. In this study we screened altered over expression of metabolic enzymes in hepatoblastoma tumors at tissue and single cell level. A hepatoblastoma tumor expression metabolic score was established and validated by machine learning; (2) Methods: Starting from Mammalian Metabolic Enzyme Database, bulk RNA-sequencing from GSE104766 dataset was investigated by supervised analyses (tumors versus adjacent liver tissue). Overexpressed enzymes in hepatoblastoma tumors were functionally enriched on KEGG metabolic database to draw a metabolic network with Cytoscape. Activated metabolic markers were used to compute a single-cell metabolic score in human and PDX hepatoblastoma samples from GSE180665 dataset (sc-RNAseq). ROC and area under curve (AUC) were computed on metabolic score. Elasticnet model tuning for metabolic marker expression was performed with r-caret on single cell transcriptome and revealed importance of individual marker to predict tumor cell status; (3) Results: Differential expression analysis on bulk transcriptome identified 287 significantly regulated enzymes between tumor and adjacent liver tissues: 59 of them were found overexpressed in tumors. 45 of the 59 over expressed enzymes were recognized in KEGG database which highlighted a main metabolic network enriched in amino acid metabolism but also carbohydrate, steroid, one carbon, purine, and glucoaminoglycan metabolisms. Based on expression of the 59 over expressed enzymes, the single cell metabolism score computed on GSE180665 dataset allowed to predict tumor cell status with and AUC of 0.98 (sensibility 0.93, specificity: 0.94). Elasticnet model tuned at 0.97 of AUC on individual marker single cell expression ranked top tumor predictive markers by decreasing importance: FKBP10, ATP1A2, NT5DC2, UGT3A2, PYCR1, CKB, GPX7, DNMT3B, GSTP1, and OXCT1; (4) Conclusion: An activated metabolic transcriptional program potentially affecting epigenetic functions was observed by bulk RNAseq in tumors of hepatoblastoma and confirmed at single cell levels in tumor cells.

Background: The risk of SARS-CoV-2 transmission to health care workers in intensive care units (ICU) and the contribution of airborne and fomites to SARS-CoV-2 transmission remain unclear. To assess the rate of air and surface contamination and identify risk factors associated with this contamination in patients admitted to the ICU for acute respiratory failure due to SARS-CoV-2 pneumonia. Methods: Prospective multicentric non-interventional study conducted from June 2020 to November 2020 in 3 French ICUs. For each enrolled patient, 3 predefined surfaces were swabbed, 2 air samples at 1 m and 3 m from the patient's mouth and face masks of 3 health care workers (HCW) were collected within the first 48 h of SARS-CoV-2 positive PCR in a respiratory sample. Droplet digital PCR and quantitative PCR were performed on different samples, respectively. Results: Among 150 included patients, 5 (3.6%, 95%CI: 1.2% to 8.2%) had positive ddPCR on air samples at 1 m or 3 m. Seventy-one patients (53.3%, CI95%: 44.5% to 62.0%) had at least one surface positive. Face masks worn by HCW were positive in 6 patients (4.4%, CI: 1.6% to 9.4%). The threshold of RT-qPCR of the respiratory sample performed at inclusion (odds ratio, OR= 0.88, 95%CI: 0.83 to 0.93, p < 0.0001) and the presence of diarrhea (OR= 3.28, 95%CI: 1.09 to 9.88, p = 0.037) were significantly associated with the number of contaminated surfaces. Conclusion: In this study, including patients admitted to the ICU for acute respiratory failure " contact route " of transmission, i.e. through fomites, seems dominant. While presence of SARS-CoV-2 in the air is rare in this specific population, the presence of diarrhea is associated to surface contamination around Covid patients. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).

Cranial neural crest cells are implicated in multiple transcriptional events at the different stages of differentiation during development. The alteration of some transcription factors expressed during neural crest development, like PAX7, could be implicated in the etiology of face malformation in murine models. Epigenetic regulation has been shown to be an important mechanistic actor in the control of timing and the level of gene expression at different stages of neural crest development. During this work, we investigated the interconnection between epigenetics and transcription factors across a diversity of human development cranial neural crest cells. Across a diversity of neural cells from human developing cranial tissues, in accordance with their proliferation stage, an alternative balance of regulation between transcription factors and epigenetic factors was identified.

Hepatoblastoma is the most common primary liver malignancy in children, with metabolic reprogramming playing a critical role in its progression due to the liver’s intrinsic metabolic functions. Enhanced glycolysis, glutaminolysis, and fatty acid synthesis have been implicated in hepatoblastoma cell proliferation and survival. In this study, we screened for altered overexpression of metabolic enzymes in hepatoblastoma tumors at tissue and single-cell levels, establishing and validating a hepatoblastoma tumor expression metabolic score using machine learning. Starting from the Mammalian Metabolic Enzyme Database, bulk RNA sequencing data from GSE104766 and GSE131329 datasets were analyzed using supervised methods to compare tumors versus adjacent liver tissue. Differential expression analysis identified 287 significantly regulated enzymes, 59 of which were overexpressed in tumors. Functional enrichment in the KEGG metabolic database highlighted a network enriched in amino acid metabolism, as well as carbohydrate, steroid, one-carbon, purine, and glycosaminoglycan metabolism pathways. A metabolic score based on these enzymes was validated in an independent cohort (GSE131329) and applied to single-cell transcriptomic data (GSE180665), predicting tumor cell status with an AUC of 0.98 (sensitivity 0.93, specificity 0.94). Elasticnet model tuning on individual marker expression revealed top tumor predictive markers, including FKBP10, ATP1A2, NT5DC2, UGT3A2, PYCR1, CKB, GPX7, DNMT3B, GSTP1, and OXCT1. These findings indicate that an activated metabolic transcriptional program, potentially influencing epigenetic functions, is observed in hepatoblastoma tumors and confirmed at the single-cell level.

Background: Hepatoblastoma, the most common pediatric liver malignancy, is characterized by significant molecular heterogeneity and poor prognosis in advanced stages. Recent studies highlight the importance of metabolic reprogramming and epigenetic dysregulation in hepatoblastoma pathogenesis. This review aims to explore the metabolic alterations and epigenetic mechanisms involved in hepatoblastoma and how these processes contribute to tumor progression and survival. Methods: Relevant literature on metabolic reprogramming, including enhanced glycolysis, mitochondrial dysfunction, and shifts in lipid and amino acid metabolism, as well as epigenetic mechanisms like DNA methylation, histone modifications, and non-coding RNAs, was reviewed. The interplay between these pathways and their potential as therapeutic targets were examined. Results: Hepatoblastoma exhibits metabolic shifts that support tumor growth and survival, alongside epigenetic changes that regulate gene expression and promote tumor progression. These pathways are interconnected, with metabolic changes influencing the epigenetic landscape and vice versa. Conclusions: The dynamic interplay between metabolism and epigenetics in hepatoblastoma offers promising avenues for therapeutic intervention. Future research should focus on integrating metabolic and epigenetic therapies to improve patient outcomes, addressing current gaps in knowledge to develop more effective treatments.

Genotype I, the penultimate HBV genotype to date, was granted the status of a bona fide genotype only in the XXIst century after some hesitations. The reason for these hesitations was that genotype I is a complex recombinant virus formed with segments from three original genotypes, A, C, and G. It was estimated that genotype I is responsible for only an infinitesimal fraction (<1.0%) of the chronic HBV infection burden worldwide. Furthermore, most probably due to its recent discovery and rarity, the natural history of infection with genotype I is poorly known in comparison with those of genotypes B or C that predominate in their area of circulation. Overall, genotype I is a minor genotype infecting ethnic minorities. It is endemic to the Southeast Asian Massif or Eastern Zomia, a vast mountainous or hilly region of 2.5 million km2 spreading from Eastern India to China, inhabited by a little more than 100 million persons belonging primarily to ethnic minorities speaking various types of languages (Tibeto-Burman, Austroasiatic, and Tai-Kadai) who managed to escape the authority of central states during historical times. Genotype I consists of two subtypes: I1, present in China, Laos, Thailand, and Vietnam; and I2, encountered in India, Laos, and Vietnam.

Hepatocellular carcinoma (HCC) is the fifth most common human malignancy and the fourth most frequent cause of cancer-related deaths worldwide. Toll-like receptors (TLRs), are known to play a key role in hepatocarcinogenesis through induction of inflammation. We aimed to investigate the association between TLR2 rs3804099, TLR4 rs4986790, rs4986791, and rs11536889 and TLR5 rs5744174 and HCC risk in a total of 306 Moroccan subjects, including 152 HCC patient and 154 controls using a TaqMan allelic discrimination assay. Our result showed that the frequency of TLR4 rs11536889 C allele was higher in control group than in HCC patients (OR = 0.52, 95% CI = 0.30-0.88, p = 0.01). Moreover, under the dominant model, we observed that CG/CC genotypes were protective factors against HCC risk (OR = 0.51, 95% CI = 0.28-0.91, p = 0.02). However, no significant differences were found in the allele and genotype frequencies of TLR4 rs4986790 and rs4986791, between HCC patients and controls. Similarly, genotypic frequencies of TLR2 and TLR5 polymorphisms did not differ significantly between HCC patients and controls. However, TLR4 haplotype analysis revealed that ACC haplotype may be protective of HCC risk in patients with HCC (OR = 0.53, 95% CI = 0.31-0.92, p = 0.02). In conclusion, our result suggest that TLR4 rs11536889 polymorphism and ACC haplotype may decrease risk of hepatocellular carcinoma in Moroccan population

Chronic liver diseases still represent a worrying public health issue in Sub-Saharan Africa. In this region, emphasis is generally made on hepatocellular carcinoma (HCC) albeit liver cirrhosis (LC) is also responsible for an important death toll. Very few studies have compared the presentation and etiologies of cancer and cirrhosis of the liver in Middle Africa. We conducted a comparative retrospective analysis of 74 and 134 cases of patients with HCC and LC treated in Libreville, Gabon. Viral or lifestyle risk factors, clinical symptoms, and biological features were compared. We observed that ages of diagnosis were 53.2 ± 15.7 years and 48.6 ± 18.6 years for HCC and LC with remarkably low M:F sex ratios (1.3–1.8). Ethanol consumption was highly prevalent in both disease types (65.0%–70.0%). Chronic viral infections with hepatitis B (HBV) or C (HCV) virus were also widespread with slight domination of the former in both diseases (43.4% vs. 34.3%, and 35.9% vs. 28.5%). Patients with HCC were presenting very late with a mean diameter of the main nodule of 84 ± 50 mm and a multifocal pattern in 72.7% of cases. HCC developed on a cirrhotic liver in 91.7% of cases. Serum AFP was frankly elevated (>400 ng/ml) in only 35.8% of HCC cases. The most striking feature of the HCC series was the contrasted contribution of distinct pathogenic etiologies involving sex, viral, metabolic, and toxic factors. A frequently dysmetabolic condition synergizing with hepatitis C (anti-HCV, 73.8% vs 22.7%, p < 0.0001) in females and a male cancer promoted by recreational toxicants and chronic hepatitis B (HBsAg, 83.5% vs 35.9%, p < 0.0001) were observed. Men with HCC were considerably younger than women (46.8 ± 14.5 years vs. 62.2 ± 12.2 years, p < 0.0001). Further studies are now warranted to identify routes of HCV transmission and if they are still fueling reservoirs of future patients. Public policies to prevent alcohol-related harm have also to be urgently implemented in Gabon.

In this study, we demonstrated in culture and in patients that HBV could be edited by APOBEC3C(S188I). This enzyme led to an enhanced editing activity in a more specific 5MODIFIER LETTER PRIMETpCpA -> 5MODIFIER LETTER PRIMETpTpA context. This constitutes a new hallmark of APOBEC3C(S188I). Single-nucleotide polymorphism in APOBEC3C (resulting in a serine to isoleucine in position 188) is present in approximately 10% of African populations and greatly enhances restriction against human immunodeficiency virus-1 and simian immunodeficiency virus by improving dimerization and DNA processivity of the enzyme. In this study, we demonstrated in culture and in infected patients that hepatitis B virus (HBV) could be edited by APOBEC3C(S188I). Using next-generation sequencing, we demonstrated that APOBEC3C(S188I) led to enhanced editing activity in 5MODIFIER LETTER PRIMETpCpA -> 5MODIFIER LETTER PRIMETpTpA context. This constitutes a new hallmark of this enzyme, which could be used to determine its impact on HBV or nuclear DNA.

BackgroundLaos is considered highly endemic for persistent infection with hepatitis B virus (HBV). To eliminate this burden, it has gradually implemented universal anti-hepatitis B immunisation of newborns over the past two decades.MethodsUsing VIKIA® HBsAg, a rapid test for the qualitative detection of the HBV surface antigen, we conducted between Sep 1st, 2020 and Aug 31st, 2021 the largest prospective prevalence survey ever in Laos. This survey included blood donors (BD, n = 42,277), patients attending care in capital and provincial hospitals (n = 37,347) including attending mothers (n = 20,548), HIV-infected patients (n = 7439, recruited from 2009 to 2020), students from the Health Sciences University (n = 609), and outpatients (n = 350) coming for diagnosis at the Center Infectiology Lao-Christophe Mérieux in Vientiane. In total, 88,022 persons were tested, representing approximately 1.22% of the national population. To reach a reasonable estimate of HBsAg prevalence in Laos, we segmented the population according to three variables, age (≤20 years as a cut-off), sex, and geographical origin. BD values were used to estimate HBsAg prevalence in patients aged <20 while hospital survey prevalence was used to estimate the prevalence in those aged older than 20 years.FindingsWe observed an HBsAg seroprevalence ranging from 2.6% in blood donors to 8.0% in HIV-infected patients. In BD, men were significantly more at risk to be carriers than women (RR = 1.2, P = 0.00063). For BD, attending mothers, or HIV-infected patients, HBsAg was significantly more prevalent in northern Laos (5.1–8.4%) than in central (2.0–8.1%) or southern parts of the country (2.2–6.9%), thereby delineating a North-to-South gradient.InterpretationWe considered that HBsAg prevalence probably ranges between 5.0% and 6.0% of the total population. Thus, we consider that Laos may no longer be highly endemic for chronic HBV infection but rather a country with intermediate endemicity.FundingThe funding sources were the Agence Universitaire de la Francophonie, the French Government, the French Institute for Sustainable Development (IRD), and European Union’s Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) – Research and Innovation Staff Exchange - (RISE) under grant agreement N° 823935.

RT-qPCR detection of SARS-CoV-2 RNA still represents the method of reference to diagnose and monitor COVID-19. From the onset of the pandemic, however, doubts have been expressed concerning the sensitivity of this molecular diagnosis method. Droplet digital PCR (ddPCR) is a third-generation PCR technique that is particularly adapted to detecting low-abundance targets. We developed two-color ddPCR assays for the detection of four different regions of SARS-CoV-2 RNA, including non-structural (IP4-RdRP, helicase) and structural (E, N) protein-encoding sequences. We observed that N or E subgenomic RNAs are generally more abundant than IP4 and helicase RNA sequences in cells infected in vitro, suggesting that detection of the N gene, coding for the most abundant subgenomic RNA of SARS-CoV-2, increases the sensitivity of detection during the highly replicative phase of infection. We investigated 208 nasopharyngeal swabs sampled in March-April 2020 in different hospitals of Greater Paris. We found that 8.6% of informative samples (n = 16/185, P < 0.0001) initially scored as "non-positive" (undetermined or negative) by RT-qPCR were positive for SARS-CoV-2 RNA by ddPCR. Our work confirms that the use of ddPCR modestly, but significantly, increases the proportion of upper airway samples testing positive in the framework of first-line diagnosis of a French population.

Laos is a landlocked country in South East Asia, ranking fifth for primary liver cancer incidence worldwide. Risk factors that might explain this worrying situation are poorly known. We conducted a review of the literature concerning the etiologies of terminal liver diseases in Laos. A double infectious burden with hepatitis B and C viruses and the liver fluke Opisthorchis viverrini seems to be the main cause of the high liver cancer incidence. Moreover, it was also suggested that mutagenic substances frequently found in tobacco, alcoholic beverages, fermented fish, and mold-contaminated cereals or nuts, which are all substances heavily consumed by Lao people, lead to the accumulation of DNA mutations in the liver cell genome causing tumor processes. However, the respective proportions of liver cancer cases attributable to each category of infections and substances consumed, as well as the histological nature of the neoplasia are still not precisely documented in Laos. The international medical and scientific communities as well as public health stakeholders should urgently consider the alarming situation of liver health in Laos to stimulate both research and subsequent implementation of prevention policies.

Objectives: The interferon (IFN) is known to bridge innate and adaptive immune responses, and to play a critical role particularly against hepatitis B virus (HBV) infection. Defects in IFN signals may result, therefore, in attenuated responses against HBV. Accordingly, polymorphisms in genes coding for immune response effectors may affect the clinical outcome of HBV infection. We analyzed the putative association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection in Moroccan patients. Methods: In this study, 237 chronic HBV (CHB) patients and 129 spontaneously resolved HBV (SRB) individuals were enrolled and genotyped using a predesigned Taqman allelic discrimination assay. Results: Our data show a significant increase of HBV DNA loads in patients with IFNL4 rs12979860 CC genotype compared to patients with CT and TT genotypes (p = 0.0008). However, there was no consistent association between IFNL4 rs12979860 polymorphism and the outcome of HBV infection. Conclusions: Although IFNL4 rs12979860 polymorphism seems to modulate circulating HBV DNA levels, it is disconnected from chronic disease progression. This observation suggests that the role of rs12979860 in liver disease is restricted to viral control and inactive in the deleterious immune pathology that affects liver tissue. Taken together, our data suggest that rs12979860 CC genotypes could be useful as a predictor of success or failure of IFN- based therapy in chronic HBV-infected patients. (C) 2021 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.