Genetic variations in toll‐like receptors 7 and 8 modulate natural hepatitis C outcomes and liver disease progression

Fakhir, Fatima-Zohra; Lkhider, Mustapha; Badre, Wafaa; Alaoui, R.; Meurs, Éliane; Pineau, Pascal; Ezzikouri, Sayeh

doi:10.1111/liv.13533

Cited by 37 publications

(34 citation statements)

References 38 publications

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“…To date, studies of the influence of TLR7 gene Gln11Leu polymorphism on the rate of hepatic fibrosis progression are limited. The results of our study are in line with a number of scientific studies [12,13,15,16], but they contradict the data of F. Z. Fakhir (2018), who describes the 11Leu allele as a profibrogenic factor, and E. Ascar (2010), who denies the influence of this polymorphism on fibrogenesis in chronic hepatitis C [10,14]. The use of the proposed clinical and genetic prognostic model allows predicting the probability of rapid hepatic fibrosis progression in men with chronic hepatitis C with high accuracy and forming a group of patients who need to receive antiviral therapy in the first place on the basis of simple characteristics, most of which are used in a routine clinical practice.…”

Section: Discussionsupporting

confidence: 76%

“…Considering the fact that chronic hepatitis C is detected more often in males, the rate of hepatic fibrosis progression is gender dependent, as well as the availability of data on the influence of the polymorphic 11Leu allele of the TLR7 gene on this process [12][13][14][15][16], scientific and practical interest represents the search for clinical genetic predictors and the creation of a prognostic model for the rapid hepatic fibrosis progression in men.…”

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confidence: 99%

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Prognostic model of rapid hepatic fibrosis progression in men with chronic hepatitis C

et al. 2019

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The aim of the research was to determine clinical and genetic predictors and to create a prognostic model for the rapid hepatic fibrosis progression in men with chronic hepatitis C. Materials and methods. А cross-sectional study which included 111 male patients with chronic hepatitis C was conducted. The patient examination program included: assessment of complaints and anamnestic data, physical examination, complete blood count, biochemical test, the stages of hepatic fibrosis according to METAVIR аnd genetic studies (detecting carriers alleles 11Gln or 11Leu of TLR7 gene in the genome of the examined men). Results. It was determined that informative predictors of rapid hepatic fibrosis progression in men with chronic hepatitis C are: ethanol use in a dose of more than 40 g/day (ОR = 2.40, P = 0.042), presence of chronic cholecystitis in past history (ОR = 2.94, P = 0.013), ALT level above 3 upper limit of normal (ОR = 2.49, P = 0.031), the levels of AST, GGT exceeding upper limit of normal (ОR = 6.94, P < 0.001 and ОR = 4.02, P = 0.001 respectively), hyperbilirubinemia (ОR = 3.13, P = 0.010) and carrier state of allele 11Gln of TLR7 gene in the genome (ОR = 3.62, P = 0.036). In order to optimize the prognosis of rapid hepatic fibrosis progression in men with chronic hepatitis C a model that demonstrated statistical significance (χ² = 44.73, P < 0.001) and high operational characteristics (sensitivity-76.8 %, specificity-74.5 %, the total number of correct predictions-75.7 %, AUC of the ROC-curve-0.828), which indicates the feasibility of its practical use, was proposed. Conclusions. An effective clinical and genetic prognostic model has been created and allows us to predict the probability of rapid hepatic fibrosis progression in men with chronic hepatitis C with high accuracy and to form a group of patients who need high priority antiviral therapy.

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Section: Discussionsupporting

confidence: 76%

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confidence: 99%

Prognostic model of rapid hepatic fibrosis progression in men with chronic hepatitis C

et al. 2019

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“…In both infections, the variant allele associated with higher disease prevalence and augmented disease progression, and with reduced response to IFNα-therapy for HCV (Oh et al, 2009;Said et al, 2014;Askar et al, 2010;Schott et al, 2007b;Fakhir et al, 2018). In all these studies, effects were most prominent in (mostly rs179008 heterozygous) females and all studies predominantly contained Caucasian individuals.…”

Section: Discussionmentioning

confidence: 97%

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

et al. 2018

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A B S T R A C TTLR7 agonists are of high interest for the treatment of cancer, auto-immunity and chronic viral infections. They are known to activate plasmacytoid dendritic cells (pDCs) to produce high amounts of Type I Interferon (IFN) and to facilitate T and B cell responses, the latter with the help of maturation markers such as CD40, CD80 and CD86. The TLR7 single nucleotide polymorphism (SNP) rs179008 (GLn11Leu), sex and chronic viral infection have all been reported to influence pDC IFN production. It is unknown, however, whether these factors also influence pDC phenotypic maturation and thereby IFN-independent pDC functions. Furthermore, it is unclear whether SNP rs179008 influences HBV susceptibility and/or clearance.Here we investigated whether the SNP rs179008, sex and HBV infection affected phenotypic maturation of pDCs from 38 healthy individuals and 28 chronic HBV patients. In addition, we assessed SNP prevalence in a large cohort of healthy individuals (n = 231) and chronic HBV patients (n = 1054).Consistent with previous reports, the rs179008 variant allele was largely absent in Asians and more prevalent in Caucasians. Among Caucasians, the SNP was equally prevalent in healthy and chronically infected males. The SNP was, however, significantly more prevalent in healthy females than in those with chronic HBV infection (42 versus 28%), suggesting that in females it may offer protection from chronic infection. Ex vivo experiments demonstrated that induction of the co-stimulatory molecules CD40 and CD86 by TLR7 ligands, but not TLR9 ligands, was augmented in pDCs from healthy SNP-carrying females. Furthermore, CD80 and CD86 upregulation was more pronounced in females independent of the SNP. Lastly, our data suggested that chronic HBV infection impairs pDC maturation. These findings provide insight into factors determining TLR7 responses, which is important for further clinical development of TLR7-based therapies.

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“…This SNP is nonsynonymous by its character and is characterized by the substitution of glutamine (Gln) for leucine (Leu) in the encoded protein. As a result, the signaling peptide of TLR7 receptor displays functional degeneracy [20]. In response to synthetic inductors in the dendrite cells and hepatocytes of the minor T allele carriers, low expression of IFNL1 mRNA, IL-10Rβ, and IL-28Rα is observed [21].…”

Section: Discussionmentioning

confidence: 99%

The Role of Human Genetic Factors in the Natural Selection of Hepatitis C Virus’ Dominant Genotype in Ethnically Close Populations of Buryats and Khalkha-Mongols

Malov¹,

Baatarkhuu²,

Огарков³

et al. 2018

Sovrem Tehnol Med

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The aim of the study was to assess the role of the innate immunity gene polymorphism in the population selection of hepatitis C virus (HCV) genotypes circulating in the ethnically close groups of Mongoloids: Buryats and Khalkha-Mongols. Materials and Methods. Nucleotide polymorphisms of innate immunity genes were identified in 400 patients with chronic hepatitis C, including 200 people belonging to the ethnic group of Mongols living in Ulaanbaatar (Mongolia) and 200 to the ethnic group of Buryats living in Ulan-Ude (Republic of Buryatia). The control group (n=531) consisted of apparently healthy people comprising 220 Buryats and 311 Khalkha-Mongols. Genetic studies of twelve single-nucleotide polymorphisms of nine genes: IFNL1 (rs30461); IFNL3 (rs12979860 and rs8099917); IFNL4 (rs368234815); CD209 (rs4804803); TLR3 (rs3775291 and rs13126816); TLR7 (rs179008 and rs179009); IFITM (rs12252); MyD88 (rs6853); IFIH1 (rs1990760) have been performed in the mentioned selections of the sick and healthy individuals. When analyzing the genetic study results, frequencies of gene alleles and their combinations in the form of genotypes have been compared. Results. The dominant prevalence of the HCV genotype 1 (98.0%) was found in the territory of Mongolia which appeared to be significantly higher (p<0.001) than its prevalence in the territory of Buryatia (66.0%). Among the genetic factors which can influence the formation of the circulating genotype structures in Buryat and Mongolian population, single-nucleotide polymorphisms in three genes (IFNL3, TLR3, and TLR7), the frequency of which differed significantly in the examined cohorts, have been detected. In the ethnical Buryat group, the search for the candidate genes in patients with chronic hepatitis C genotype 1 and non-1 (2 or 3, 2/3) has established that T allele of rs179008 TLR7 gene occurs 2 times more often in women with chronic hepatitis C infection caused by genotype 2/3 than by genotype 1 (p=0.04). Conclusion. A low prevalence of HCV genotypes 2 and 3 among the population in the territory of Mongolia is likely to be caused by a rare frequency of the mutant T allele of TLR7 gene (rs179008) associated with the predisposition to HCV-2/3 infection, i.e. the situation that has been demonstrated in our work using the ethnical group of Buryats as an example.

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Genetic variations in toll‐like receptors 7 and 8 modulate natural hepatitis C outcomes and liver disease progression

Cited by 37 publications

References 38 publications

Prognostic model of rapid hepatic fibrosis progression in men with chronic hepatitis C

Prognostic model of rapid hepatic fibrosis progression in men with chronic hepatitis C

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

The Role of Human Genetic Factors in the Natural Selection of Hepatitis C Virus’ Dominant Genotype in Ethnically Close Populations of Buryats and Khalkha-Mongols

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