Implication of genetic variation at the promoter and exon1 of UGT1A1 in occurrence of cholelithiasis in Tunisia.

International audienceBilirubin is conjugated with glucoronic acid in the liver by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms at the promoter region or exon1 of UGT1A1 gene result in unconjugated hyperbilirubinemia and could be at the origin of gallstone formation. The purpose of this study is to determine whether polymorphisms in the promoter area and exon 1 of UGT1A1 can be considered as a risk factor for lithogenesis. Our study involved 76 patients with cholelithiasis as well as 141 unaffected subjects. For each subject an analysis of the bilirubin parameters was performed. We screened genetic variation in the promoter and exon1 UGT1A1 namely the A (TA) nTAA and the six following SNPs: 44T>G, 101C>A, 115C>G, 145C>T, 211G>A and 222 C>A by PCR/sequencing. Our findings show that subjects with (TA)(7) or (TA)(8) variant in their genotypes are associated with high bilirubin level. Furthermore, the comparison between patients and controls according to A(TA)nTAA variation demonstrated that (TA)(6)/(TA)(7) and (TA)(7)/(TA)(7) genotype and (TA)(7) and (TA)(8) alleles were significantly associated with an increased risk of gallstone diseases p=0.0017, p= 6.1 10(-6), p=1.5 10(-6) and p=0.025 respectively. However, polymorphisms in exon1 were normal in all studied subjects except for the 211G>A which appears to be associated with a protective effect p=7.910(-9); OR=0.03, CI95% (0.001-0.158)

rs11886868 and rs4671393 of BCL11A associated with HbF level variation and modulate clinical events among sickle cell anemia patients

International audienceAims: Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia (SCA) by inhibiting deoxy sickle hemoglobin (HbS) polymerization. HbF genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Herein, we aimed to determine whether two functional polymorphisms of BCL11A are implicated in the variation of HbF and clinical events in SCA Tunisian patients. Material and methods: The studied population consisted of 148 SCA patients with SS phenotype. The group of patients was divided into two subgroups according to the threshold point of %HbF which is 15%. Genotyping of rs11886868 and rs4671393 was performed using PCR/Sequencing. To test for trait association with the candidate SNPs, genotype and allele frequencies between `group who had %HbF 15' (controls) were compared using Pearson's chi-square test (compare 2, version 1.02). The association of each genotype and the combined genotype with complications was performed by logistic regression test. Results: Our findings showed that the majority of patients carried genotype CT of rs11886868 and genotypes AG and GG of rs4671393 present HbF level < 15%. RR = 0.08, RR = 0.176, and RR = 0.189, respectively. The results showed a significant association between the alleles T of rs11886868 and G of rs4671393 and %HbF < 15% with P = 0.016; RR = 0.39 and P = 8.9 x 10(-3): RR = 0.567, respectively. Interestingly, the C allele of the rs11886868 and the A allele of the rs46713939 were associated with an ameliorated phenotype in patient's SCA. The combination of the genotypes GG and CT explains more phenotypic variance than the sum of the two BCL11A SNPs taken individually

Association of rs1319868, rs1567811 and rs8041224 of gene with infection among sickle cell anemia Tunisian patients

Background and aimSickle cell anemia (SCA) is characterized by variable patterns of clinical expression. Polymorphisms linked to different genes have been associated with specific complications of the disease. Herein, we focused on the study of the association of 4 polymorphisms of Insulin like Growth Factor 1 receptor (IGF1R) gene with infections, which are the major cause of death in SCA.Material and methodsThis study involved 116 sickle cell patients among whom 58 SS have the same confirmed infectious phenotype. Allele-Specific PCR was performed for the study of rs1319868, whereas the PCR/sequencing method was carried out for rs1567811, rs2872060 and rs8041224.ResultsThe results showed that rs1319868 and rs1567811 were associated with a decreased risk of infection among SS patients (p=0.038, RR=0.54; p=0.044, RR=0.56, respectively). Interestingly, the combination of different genotypes showed the association of the genotype GT of rs1319868 and the genotype CC of rs8041224 with further decreased infection risk in SCA (p=0.028, RR=0.04).ConclusionThese significant associations of IGF1R SNPs with infection suggest that this gene could play an important role in the immune function in SCA

Genetic link with cholelithiasis among pediatric SCA Tunisian patients: Examples of UGT1A1, SLCO1A2 and SLCO1B1

International audienceAims and background: Hyperbilirubinemia is often observed in chronic hemolysis and results in the formation of pigment cholelithiasis that could be increased by the presence of defected enzymes involved in the bilirubin metabolism. Indeed, this is the first report that interested in the study of polymorphisms in genes encoded for enzymes involved in the bilirubin metabolism: rs 4149056 of SLCO1B1 and rs4149000 of SLCO1A2 in combination with rs8175347 and rs887829 of UGT1A1 in order to find a correlation between the polymorphisms studied and the presence of gallstones in a population of sickle cell anemia (SCA) pediatric Tunisians. Material and methods: Our study involved 102 unrelated Tunisian subjects. All SCA patients are children (less than 16 years old) and were characterized by hyperbilirubinemia and 52 of them have cholelithiasis. The polymorphisms of the candidate genes were analyzed for all subjects by PCR/sequencing. Genotype and allele frequencies between cases and controls were compared using Pearson's chi-square test with a significance threshold of P < 0.05 (compare 2, version 1.02). Results: The novelty of this report is that children carrying the combined genotype of the rs studied: (TA7TA7)/TT/TC/GA have a higher risk to develop gallstones (P = 0.0027, RR = 18.27 (20.0061-915.28)). Conclusion: Altogether our data provide the implication of UGT1A1 and SLCO1A2 in sickle cell anemia-related cholelithiasis

Simulating aerosols over Arabian Peninsula with CHIMERE : Sensitivity to soil, surface parameters and anthropogenic emission inventories

A three dimensional chemistry transport model, CHIMERE, was used to simulate the aerosol optical depths (AOD) over the Arabian Peninsula desert with an offline coupling of Weather Research and Forecasting (WRF) model. The simulations were undertaken with: (i) different horizontal and vertical configurations, (ii) new datasets derived for soil/surface properties, and (iii) EDGAR-HTAP anthropogenic emissions inventories. The model performance evaluations were assessed: (i) qualitatively using MODIS (Moderate-Resolution Imaging Spectroradiometer) deep blue (DB) AOD data for the two local dust events of August 6th and 23rd (2013), and (ii) quantitatively using AERONET (Aerosol Robotic Network) AOD observations, CALIPSO (Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation) aerosol extinction profiles, and AOD simulations from various forecast models. The model results were observed to be highly sensitive to erodibility and aerodynamic surface roughness length. The use of new datasets on soil erodibility, derived from the MODIS reflectance, and aerodynamic surface roughness length (z0), derived from the ERA-Interim datasets, significantly improved the simulation results. Simulations with the global EDGAR-HTAP anthropogenic emission inventories brought the simulated AOD values closer to the observations. Performance testing of the adapted model for the Arabian Peninsula domain with improved datasets showed good agreement between AERONET AOD measurements and CHIMERE simulations, where the correlation coefficient (R) is 0.6. Higher values of the correlation coefficients and slopes were observed for the dusty periods compared to the non-dusty periods

Phenotypic and molecular genetic analysis of Pyruvate Kinase deficiency in a Tunisian family

Pyruvate Kinase (PK) deficiency is the most frequent red cell enzymatic defect responsible for hereditary non-spherocytic hemolytic anemia. The disease has been studied in several ethnic groups. However, it is yet an unknown pathology in Tunisia. We report here, the phenotypic and molecular investigation of PK deficiency in a Tunisian family. This study was carried out on two Tunisian brothers and members of their family. Hematological, biochemical analysis and erythrocyte PK activity were performed. The molecular characterization was carried out by gene sequencing technique. The first patient died few hours after birth by hydrops fetalis, the second one presented with neonatal jaundice and severe anemia necessitating urgent blood transfusion. This severe clinical picture is the result of a homozygous mutation of PKLR gene at exon 8 (c.1079G>A; p.Cys360Tyr). Certainly, this research allowed us to correlate the clinical phenotype severity with the identified mutation. Moreover, this will help in understanding the etiology of unknown anemia in our country

Retrospective Phylodynamic and Phylogeographic Analysis of the Bluetongue Virus in Tunisia

Bluetongue virus (BTV) is an arbovirus considered as a major threat for the global livestock economy. Since 1999, Tunisia has experienced several incursions of BTV, during which numerous cases of infection and mortality have been reported. However, the geographical origin and epidemiological characteristics of these incursions remained unclear. To understand the evolutionary history of BTV emergence in Tunisia, we extracted from Genbank the segment 6 sequences of 7 BTV strains isolated in Tunisia during the period 2000 to 2017 and blasted them to obtain a final dataset of 67 sequences. We subjected the dataset to a Bayesian phylogeography framework inferring geographical origin and serotype as phylodynamic models. Our results suggest that BTV-2 was first introduced in Tunisia in the 1960s and that since 1990s, the country has witnessed the emergence of other typical and atypical BTV serotypes notably BTV-1, BTV-3 and BTV-Y. The reported serotypes have a diverse geographical origin and have been transmitted to Tunisia from countries in the Mediterranean Basin. Interserotype reassortments have been identified among BTV-1, BTV-2 and BTV-Y. This study has provided new insights on the temporal and geographical origin of BTV in Tunisia, suggesting the contribution of animal trade and environment conditions in virus spread