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We describe a Tunisian family carrier of the same rare mutation iniTARDBP/ibut developing different neurodegenerative disease with heterogenous features. We explored the possible genetic modifiers leading to the observed intrafamilial phenotypic variability. Genetic analysis identifiediTARDBP/ip.G294A mutation among4 members. Additionally, the ALS case was muted iniGBA/i. While the three cases of AD were carriers ofiPRKN/iandiGBA/imutations. Finally, the FTD-parkinsonism patient was mutated foriLRRK2/ip.G2019S that might increase his susceptibility to develop Parkinsonism spectrum. Genetic variants ofiTARDBP/imay influence the clinical manifestation in ALS case.

We previously reported on the association between ESR1 and ESR2 gene variants and heightened risk of breast cancer (BC). Here we investigated the association of common ESR1 and ESR2 gene variants with triple negative BC (TNBC).This retrospective case-control study involved 488 BC patients (130 TNBC, 358 non-TNBC patients). ESR1 (rs2234693, rs9340799, rs3020314, rs3798577) and ESR2 (rs928554, rs944459, rs4986938, rs1256049, rs1256030, rs1271572) genotyping was done by real-time PCR.While minor allele frequencies (MAF) of ESR1 variants were comparable between TNBC and non-TNBC subjects, significantly higher ESR2 rs1256049 MAF was seen in TNBC patients. Significantly higher frequency of ESR1 rs3798577 T/C and C/C genotypes were noted in TNBC cases, and significant differences were seen in ESR2 rs928554, rs1256049, and rs1271572 genotype distribution. Increased TNBC risk was associated with ESR1 rs3798577 T/C and C/C genotypes according to codominant and dominant models, while positive association of ESR2 rs928554 with TNBC was seen according to codominant and recessive models, and positive association of ESR2 rs1256049 with TNBC was seen according to codominant and dominant models. Positive interactions were noted between ESR2 rs1271572-ESR1 rs3020314, ESR2 rs1271572-ESR1 rs9340799, and ESR2 rs1271572-ESR1 rs2234693, ESR2 rs4986938-ESR1 rs2234693, and ESR2 rs928554-ESR1 rs9340799. Haplotype analysis confirmed the positive association of ESR1 CATT with TNBC, while ACGGCTC and ACGGTT ESR2 haplotypes were positively associated with TNBC.Results of this study confirmed the association of unique ESR1 and ESR2 genetic variants with altered risk of TNBC. This suggests possible diagnostic and prognostic role of these variants with TNBC independent of their association with BC.

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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease. To date, mutations in more than 30 genes have been linked to familial ALS forms. However, no mutational screenings have been reported in African populations so far. We aimed to investigate the presence of rare genetic variants in the 4 most common ALS causative genes among a Tunisian cohort. Patients were screened for mutations in SOD1 (exons 1-5), TARDBP (exon 6), FUS (exons 5, 6, 13/14, and 15). Juvenile ALS (JALS) patients were screened also for ALS2 (exons 3, 10, 28). Analysis of C9ORF72 was conducted by fluorescent amplicon-length analysis and repeat-primed PCR. We analyzed 197 Tunisian ALS patients, including 11 familial forms (fALS) with 17 ALS cases, 167 sporadic (sALS) and 13 JALS cases. The pathogenic variant TARDBP p.G294A mutation was reported among 18 patients. Repeat expansion in C9orf72 was recorded in 9 patients. Interestingly, 2 unrelated patients carried a double mutation in both C9orf72 and TARDBP genes. Finally, the p.Asp91Val mutation in SOD1 was identified among 4 cases in homozygous state including 3 sALS and 1 familial JALS with recessive inheritance. No pathogenic variants in FUS were identified, nor ALS2 variants in JALS cases. In our Tunisian cohort the most frequently mutated gene is TARDBP (9.4%), followed by C9orf72 (3.9%) and SOD1 (2.1%). Our study broadens the mutational spectrum in patients with ALS and defines for the first time the mutational frequency of the main ALS genes in patients of African ethnicity.

Objective: To describe the phenotypic heterogeneity of amyotrophic lateral sclerosis (ALS) in Tunisian patients, and to define the sociodemographic features, treatments, and survival rate with ALS....

Atypical Parkinsonian syndromes (APS) encompass a spectrum of neurodegenerative diseases including dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS). The effects of the Apolipoprotein E (APOE) gene on APS clinical features are controversial and understudied in several populations. We aimed to explore the influence of APOE genotype on clinical features in an APS Tunisian cohort.We included clinically diagnosed APS patients genotyped for APOE, and analyzed the clinical and APOE genotype associations.A total of 328 APS patients were included, comprising 184 DLB, 58 PSP, 49 MSA, and 37 CBS. Significant differences in initial Mini-Mental State Examination and Frontal Assessment Battery scores according to APOE genotypes (P=0.05 and 0.0048) were found. Executive dysfunction (P=0.026) disorientation (P=0.025), and hallucinations (P0.001) were more pronounced among APOE-ɛ4 carriers particularly in DLB. Memory disorders were also correlated to APOE-ɛ4 allele (P=0.048) and were more frequent among DLB and PSP carriers. Depression was associated to APOE-ε4 (P=0.042), more markedly in APOE-ε4-CBS and MSA carriers.Our findings suggested a role of APOE-ε4 in defining a more altered cognitive phenotype with variable degrees across subgroups in APS patients, especially in DLB carriers. This effect mainly concerned executive, memory and orientation functions as well as hallucinations.

Amyotrophic lateral sclerosis (ALS) is rare in Tunisia, where access to new etiopathogenic treatment is still limited. In this review, we examine the existing model of care for ALS patients in Tunisia, the law that governs ALS care and how multidisciplinary care is delivered. We also shed light on the clinical particularity of Tunisian ALS patients. We believe that funding challenges for ALS care, improvement of ALS awareness and increased knowledge for ALS management are required. The current challenges of ALS in Tunisia are to ensure coordinated interprofessional care and establish an interdisciplinary model care for people with ALS and their family caregivers as key stakeholders and decision markers.

Background Colorectal cancer (CRC) is the third most diagnosed malignancy worldwide. The global burden is expected to increase along with ongoing westernized behaviors and lifestyle. The etiology of CRC remains elusive and most likely combines environmental and genetic factors. The Kv2.1 potassium channel encoded by KCNB1 plays a collection of roles in malignancy of cancer and may be a key factor of CRC susceptibility. Our study provides baseline association between Tunisian CRC and interactions between KCNB1 variants and lifestyle factors. Methods A case-control study involving 300 CRC patients, and 300 controls was conducted Patients were carefully phenotyped and followed till the end of study. KCNB1 genotyping was confirmed by Sanger sequencing. Bivariate and multivariable logistic regression analyses were used to assess the clinical status, lifestyle and study polymorphisms association with CRC. Results We noted significant gender association with CRC occurrence. Moreover, CRC risk increases with high meat and fat consumption, alcohol use and physical activity (PA). Carriage of rs1051296 A/G and both rs11468831 ins/del and del/del genotypes (p p = 0.01) with CRC susceptibility regardless of patients’ gender while rs3331 T/C (p = 0.012) was associated with females. Stratification study according to malignancy site; Rectal Cancer (RC) and Colon Cancer (CC), reveals increasing RC risk by gender and high meat and fat consumption, alcohol use and PA. However, additional association with high brine consumption was noted for CC. The rs1051295 A/G (p = 0.01) was associated with RC risk. Increased CC risk was associated with carriage of rs1051295 A/G, rs11168831 (del/del) and (ins/del) genotypes. Conclusion The risk of CRC increases with modifiable factors by Western influences on Tunisian lifestyle such as alcohol use, high fat consumption and possibly inadequate intake of vegetables. In addition, KCNB1 polymorphisms also markedly influence CRC susceptibility. Our study establishes key elements of a baseline characterization of clinical state, Western influenced lifestyle and KCNB1 variants associated with Tunisian CRC.

Introduction Data on epidemiology of atypical parkinsonian syndromes (APS) in North African countries are limited. Our objective was to study the epidemiological features of APS in a Tunisian population. Methods We conducted a 17‐year retrospective cross‐sectional descriptive study in the Department of Neurology at Razi University Hospital. We included all patients responding to consensus diagnosis criteria of APS. We recorded demographic and clinical data. Group differences were assessed with a post hoc ANOVA with a Bonferroni error correction. Results We included 464 APS patients. Hospital prevalence of APS among all parkinsonism cases was 20.6%. Mean annual increase of incidence defined as newly diagnosed APS cases per year reached 38.8%/year. APS were divided into 4 etiological subgroups: dementia with Lewy bodies (DLB; 56.7%); progressive supranuclear palsy(PSP; 16.2%); multiple system atrophy (MSA; 14.6%); and finally corticobasal syndrome (CBS; 12.5%). Sex‐ratio was 1.2. This male predominance was found in all subgroups except MSA (p = .013). Mean age at onset was 68.5 years, most belated in DLB (69.7 years; p 70 years) in 50.7% of patients and was significantly associated with DLB subgroup (p = .013). Inaugural parkinsonism was associated with CBS and MSA (p = .0497), and gait disorders at disease onset were associated with PSP and MSA (p = .0062). Cognitive and mood disorders were more marked in DLB and most preserved in MSA. Consanguinity was more marked in CBS (p = .037), and family history of dementia and psychiatric diseases was more common in DLB. Thirty‐seven families with similar cases of APS were identified. Conclusions This is the largest African epidemiological study on APS. In our population, APS were frequent and dominated by DLB. The age of onset of parkinsonism was the most decisive feature for differential diagnosis., In this paper, we described the largest cohort of atypical parkinsonian syndromes (APS) ever reported in both sub‐Saharan and North African countries comprising 464 Tunisian patients with APS. In our population, APS were frequent and dominated by DLB. The age of onset of parkinsonian syndrome was the most decisive feature for differential diagnosis.

Objectives: Interleukin-10 (IL-10) plays an important role in the immunity to hepatitis C virus (HCV). Insofar as IL-10 variants are associated with altered levels of IL-10, previous studies that examined the association of IL-10 polymorphisms with the susceptibility to and progression of chronic HCV, and response to anti-viral treatment were inconsistent. We investigated the association between common IL-10 variants in the intron and the promotor region with HCV and associated features. Methods: Study subjects comprised 120 patients infected with HCV-1b, and treated with Peg-IFN/RBV. Genotyping of six IL-10 promoter variants in the intron region (rs1878672, rs1554286, rs1518111) and promotor region (rs1800872, rs1800871, rs1800896) were done by real-time PCR. Results: Compared to G/G, carriage of IL-10 rs1800896 (-1082A/G) A/A genotype was more frequent in patients with sustained virological response (SVR). The decline in viral load over the first 12 weeks of treatment was more pronounced in rs1800896 A/A genotype carriers, compared to G/G genotype carriers, and was irrespective of the treatment dosage. Carriage of rs1800896 A/A genotype was positively associated with improvement in viral load decline, which was simultaneous, with and without carriage of the common favourable IL-28B variant. Carriage of both IL-10 rs1800896 G/G and IL-28B non-favourable genotype was associated with twice the risk of getting slow decline of viral load during treatment. Haploview analysis identified ACGCTA and CCGCTG haplotypes to be linked with excellent PegIFN/RBV cure rate, and complete HCV eradication. On the other hand, ACGCTG and CCGCTA haplotypes were associated with resistance to PegIFN/RBV treatment. Conclusion: IL-10 rs1800896 variant markedly influences the clinical outcome of HCV infection, and is a determinant of the response to HCV treatment.

Aim of the study: Several studies implicated altered inflammatory response in the susceptibility to ovarian cancer, and polymorphisms in inflammatory cytokines were shown to play an important role in the development of malignancies, including ovarian cancer (OC). Here we investigated the relationship between polymorphisms in IL-1 (-511C>T), IL-1RN VNTR, TNF- (-308G>A), and TNF RII (-322 VNTR) and OC risk in Tunisian women. Methods and results: Study subjects comprised 62 OC patients and 126 healthy women. Genotyping was done from genomic DNA obtained from blood simple by PCR. Positive association between IL-1RN (-VNTR) A1 allele (p = 0.0069; OR = 2.04; 95% CI:1.17-3.58) and OC risk, while negative association was seen with the A3 allele (P = 0.0034; OR = 0.09; 95% CI: 0.00-0.64), suggesting a protective role by the A3 allele. For IL-1 (-511C>T), homozygous C/C genotype was associated with significantly increased risk of OC (p = 0.0002; OR = 4.14; 95% CI: 1.77-9.76), while heterozygote C/T genotype was linked with reduced risk of OC (p = 0.0033; OR = 0.40; 95% CI: 0.20-0.78). Furthermore, TNF- -308A allele was significantly associated with heightened risk of OC (p = 0.016; OR = 1.70; 95% CI: 1.08-2.69), and homozygote G/G genotype was associated with decreased risk of OC (p = 0.0018; OR = 0.25; 95% CI: 0.09-0.66). In contrast, TNFRII (-322 VNTR) polymorphism was not associated with altered OC risk in the studied group. Conclusions: The significant association between IL-1RN VNTR, IL1- (-511), TNF- (-308) and OC susceptibility in Tunisian women confirms a role for altered inflammatory response in ovarian cancer pathogenesis.

Introduction Le role genetique de l’apolipoproteine E (ApoE) dans la maladie d’Alzheimer est actuellement reconnu. Cependant son role reste controverse dans le developpement et l’expression de la paralysie supranucleraire progressive (PSP). Objectifs Etudier le role du genotype de l’ApoE dans le risque de survenue et l’expression phenotypique de la PSP. Patients et methodes Il s’agit d’une etude retrospective descriptive et analytique sur une periode de 16 ans (2003–2018) au service de Neurologie du CHU Razi, incluant les patients suivis pour PSP selon les criteres de MSD–PSP de 2017 et 64 temoins sains, chez qui une etude genetique de l’ApoE a ete faite. On a decrit les caracteristiques demographiques, cognitives et les phenotypes cliniques de nos patients. On a analyse leurs correlations avec les genotypes de l’ApoE. Resultats Nous avons inclus 50 patients (sex-ratio = 1,4 ; âge moyen : 67,4 ans). Neuf phenotypes cliniques etaient retrouves. Sur le plan genetique, l’allele ɛ3 de l’ApoE etait le plus frequent (88 %). Les porteurs de l’ApoE ɛ4 (34 %) presentaient un risque statistiquement accru de developper une PSP (OR : 1,74, IC95 % : 1,69–1,86, p = 0,049). Il n’y avait pas de correlation significative entre le genotype et les caracteristiques cliniques cognitives et demographiques de la PSP, ni les differents phenotypes de la maladie. Discussion Notre etude a montre une association significative de l’ApoEɛ4 avec un risque accru de PSP. Les donnees concernant le role de d’ApoE dans la PSP sont mitigees et il s’agit plutot de l’allele ApoEɛ2 qui est plus frequent dans la PSP. Il n’existait pas de correlation entre le genotype de l’ApoE et les phenotypes de la PSP dans notre population. Conclusion L’allele ApoEɛ4 etait associe au risque de survenue de la PSP sans correlation avec ses phenotypes. Des etudes plus larges permettraient de mieux etayer le role de l’ApoE.

The KCNB1 gene variants were differentially associated with cancers. However, their association with colorectal cancer has not yet been explored. We investigated the contribution of the KCNB1 gene variants rs3331, rs1051295, and indel (insertion/deletion) rs11468831 Polymorphism as predictors of the treatment response in colorectal cancer patients. A retrospective study, which involved 291 Tunisian colorectal cancer patients (aged 60.0 ± 13.1 years), who were stratified into responder and non-responder groups, according to TNM stages and their responsiveness to chemotherapy based on fluorouracil. KCNB1 genotyping was performed with amplification-refractory mutation system–polymerase chain reaction, and was confirmed by Sanger sequencing. Sex-specific response was found and colorectal cancer females are less likely to achieve a positive response during the chemotherapy strategy, compared to males. Weight and body mass index, tumor size, and tumor localization are considered as predictive factors to treatment responsiveness. Carriage of rs11468831 Ins allele was significantly associated with successful therapy achievement ( p adjusted

Chronic infection with hepatitis B (HBV) and C virus (HCV) is linked with a pro-inflammatory state, predisposing to cirrhosis and liver cancer, particularly hepatocellular carcinoma (HCC). A role for Toll-like receptor (TLR) signalling in hepatocarcinogenesis was recently documented. We hypothesised a link TLR3 and TLR4 polymorphisms and HCC, as surrogates for the significance of TLR signalling in the promotion and initiation of HCC.We recruited 174 HCV-infected patients, 100 HBV-infected patients and 360 healthy control subjects. TLR3 (rs3775290) and TLR4 (rs4986790) genotyping was done by PCR-restriction fragment length polymorphisms (PCR-RFLP), LFTs and AFP by standard routine techniques. Liver fibrosis was assessed clinically by the Fibrotest and Actitest.The TLR3 rs3775290 minor T genotype was linked with increased risk of chronic HBV (P = 0.05) and HCV (P = 0.031) infection. The TLR4 rs4986790 minor G genotype was linked with significantly increased risk for HBV/HCV chronic infection (P0.001). Subgroups analyses indicated decreased risk of HBV-related HCC in relation to TLR3 rs3775290 CC/CT genotype (P = 0.022), with increased risk ascribed to the minor (T) allele (P = 0.04). Likewise, TLR4 rs4985790 minor (GG) genotype was positively associated with HBV-linked HCC (P0.001). Furthermore, a link between TLR3 TT (P0.001) andTLR4 GG (P = 0.04) minor genotypes was noted in relation to increased risk of HCV-related disease.TLR3 and TLR4 polymorphisms are promising biomarkers of liver cirrhosis and cancer associated with HBV and HCV infection.

Background and aim Epidemiological studies suggested that ethnic/racial background influences the associations of altered leptin secretion and leptin gene (LEP) polymorphisms with polycystic ovary syndrome (PCOS). We investigated the association between LEP variants and plasma leptin levels with PCOS in Tunisian and Bahraini Arab women. Subjects and methods Retrospective case-control study, involving 255 PCOS cases and 253 control subjects from Bahrain, and 320 women PCOS cases and 447 controls from Tunisia. LEP genotyping was done by allele exclusion on real-time PCR. Results Minor allele frequencies of rs10487506, rs7799039, rs2167270, rs12706832, and rs10954173 LEP variants were not significantly different between PCOS cases and control women among Bahraini and Tunisians, even before applying the Bonferroni correction. Similarly, the genotype distribution of the tested LEP variants was comparable between women with PCOS and control women among Bahraini and Tunisian subjects. None of the tested LEP variants was linked with altered leptin serum concentrations. However, five-locus haplotype analysis identified GGGGG and GAGGG haplotypes to be positively, and haplotype AAGGG to be negatively associated with PCOS in Bahraini women, after adjusting for HOMA-IR. No LEP haplotype associated with PCOS was identified in Tunisians. Conclusion This is the first study to document differential contribution of LEP gene variants with PCOS according to ethnic/racial background of study subjects, highlighting the need for controlling for ethnicity in genetic association studies.

Accumulative epidemiological evidence suggests that polymorphisms of Toll-like receptors signaling pathway elucidated the cellular and molecular mechanisms of human diseases whose gaining a primordial importance. The aim of our study is to identify the role of TLR 2 (-196 to -174 del), TLR 3 (1377 C>T), TLR 4 (Asp299Gly) and TLR 9 (G2848A) gene polymorphisms with the evolution of cervical cancer in Tunisian women. Blood samples were collected from histopathologically confirmed patients with cervical cancer and unrelated healthy female controls of similar ethnicity. Genotyping of the analyzed polymorphisms were done using Polymerase Chain Reaction and Restriction Fragment Length Polymorphism. For the TLR 2, Ins/Ins genotype is a protector factor [p = 0.006; OR: 0.35(0.16-0.73)] and the dominant genotype of TLR 3 increased the risk of CC in stage (III+IV); C/C versus C/T [p = 0.033; OR: 2.03(1.00-4.13)] and C/C versus C/T+T/T [p = 0.036; OR: 1.93(1.00-3.74)]. For TLR 4, the dominant genotype Asp/Asp is implicated in the occurrence of CC in stage (I+II) [p = 0.000; OR: 4.55(1.58-13.06)], [p = 0.001; OR: 3.49(1.44-8.45)] and in stage (III+IV) [p = 0.038; OR: 3.77(0.87-16.29)], [p = 0.007; OR: 5.21(1.65-16.46)] and the major allele Asp is a risk factor for the development of tumor in stage (I+II). The TLR2 Ins/Del genotype is associated with tumor evolution to stage (III+IV) [p = 0.003; OR: 3.00 (1.22-7.35)] and the genotypes Gly/Gly and Asp/Gly+Gly/Gly and Gly allele of TLR 4 are implicated in tumor evolution to the advanced stages. Further, TLR 2, TLR 3, TLR 4 and TLR 9 gene polymorphisms are implicated in the modulation of CC risk due to tobacco usage and statue of menopause among cases. Our study suggests a relationship between the incidence of the TLR2, TLR 3, TLR 4 and TLR9 mutations and the clinical progression of CC according to the FIGO classification. However, future studies with different demographic and clinical characteristics in ethnically diverse populations may provide a more comprehensive involvement of innate immunity in cervical cancer etiology in women worldwide.

The present study was undertaken to investigate the association between Hepatitis B Virus (HBV) infection and polymorphisms of tumour necrosis factor alpha TNF-α -308 G>A, TNF-α -238 G>A and TNF RII VNTR (p75) gene promoter in a Tunisian population. Blood samples were collected from 100 Tunisian patients with HBV infection, 45 with Chronic Hepatitis (CH), 36 with Liver Cirrhosis (LC), 15 with Hepatocellular Carcinoma (HCC) and 200 healthy individuals of similar ethnicity. Genomic DNA was extracted from peripheral blood leukocytes. Genotyping of the analysed polymorphisms was performed using Amplified Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR), Restriction Fragment Length Polymorphism (RFLP) and Variable Number Tandem Repeat PCR (PCR-VNTR). The variant homozygotes -308 GG were associated with 50% decreased risk of HBV chronic infection (GG vs AA+GA; p=0.010; OR=0.50; 95%CI=0.29-0.85). However, the carriers of minor allele -308 A have higher risk (1.5 times) to develop a chronic infection than other patients (p=0.027; OR=1.46; 95%CI=1.04-2.06). The minor allele of -238 polymorphism was positively associated with virus resistance and the development of chronic infection (p=0.043; OR=1.42; 95%CI =1.01 1.99). The distribution of -308, -238 and TNF RII VNTR (p75) among the three groups differed significantly. For HCC groups, there were statistically significant differences in allele distribution in -308, -238 respectively in which A allele remains a risk factor for HBV evolution to HCC (p=0.008 and p=0.026). Haplotype analysis revealed that TNF-α (-308A; -238A) was significantly associated to HBV chronic infection and moreover to disease aggravation to HCC stage. Our findings imply that variations in the genes governing the levels of constitutive and inducible TNF-α and TNF RII might be an important risk factor, which could explain the variable outcomes of HBV infection.

Objectives TLRs are one of the most studied families of pathogen recognition receptors (PRRs) and play a pivotal role during HCV infection. The binding of ligands to TLRs on antigen presenting cells (APCs) leads to secretion of inflammatory cytokines, such as IL6, and induction of the acquired immunity response. Therefore, it has become necessarily to harness the TLRs properties’ on therapeutically tools to enhance the HCV treatment response. Herein, we investigated the association between TLR3, TLR4 variants and nine IL-6 polymorphisms, and response to anti-viral treatment during HCV infection. Methods Study subjects comprised 120 patients infected with HCV-1b and treated with Peg-IFN/RBV. Genotyping of nine IL-6 variants were done by real –time PCR and genotyping of TLRs polymorphisms were done by RFLP-PCR. Results High frequency of TLR3 rs3775290 C/C genotype and TLR4 rs4986790 A/A genotype were noticed among patients with sustained viral response compared to Non-responder patients. The genetic association of TLR3 and TLR4 variants was evidenced by the improvement in the kinetics of viral load decline, with superiority of TLR3 compared to TLR4. Among, nine polymorphisms studied on IL-6 only rs1800796, rs2069845 and rs1880242 were associated with sustained viral response. Our study reports also that the common favourable IL-28B variant is essential for TLR-activated antiviral protection. Conclusion TLR3 and TLR4 are involved in the pathogenesis of viral infections. TLR3 may be better suited than TLR4 to activate anti-viral program. Moreover, we propose that the Th2 cytokine, IL-6, constitutes a determinant of the outcome of therapy in HCV patients.

Introduction Les interactions entre l’âge, le sexe et le genotype de l’apolipoproteine E (APOE), les trois principaux facteurs de risque de la maladie d’Alzheimer (MA), ne sont que partiellement elucidees. Objectifs Determiner l’effet du genotype APOEɛ4 sur l’âge de debut, l’evolution de la maladie et la forme clinique dans une cohorte tunisienne de MA en fonction des differentes tranches d’âge. Patients et Methodes Dans une etude transversale descriptive et retrospective de 2016 patients MA, nous avons inclus 500 patients ayant eu un genotypage APOE. Nous avons etudie l’effet du genotype APOE sur quatre tranches d’âge en fonction de l’âge de debut de la maladie ( 80 ans). Un modele de regression de Cox a ete realise pour tester l’effet du genotype APOE dans chacun des quatre groupes d’âge. Resultats La relation etait significative entre l’âge au debut et la duree d’evolution de la maladie plus courte chez les patients d’âge 70 ans (p Discussion Notre etude a confirme l’effet âge-dependant en forme de U de l’APOEɛ4 sur la duree d’evolution de la maladie. L’accentuation de cet effet chez les porteurs de 2 copies APOEɛ4 suggere son caractere dose-dependant surtout chez les plus jeunes. L’association de cet allele a des formes amnesiques a un âge Conclusion L’effet de l’allele APOEɛ4 sur la duree d’evolution et la forme clinique de la MA est dose- et âge-dependant surtout chez les malades les plus jeunes de sexe feminin.

Introduction Bien qu’il soit l’un des mouvements anormaux les plus frequents, aucune mutation causale n’a ete reproductible dans le tremblement essentiel (TE). Le gene TREM2 a ete implique dans d’autres maladies neurodegeneratives. Objectifs Etudier toutes les variations localisees sur l’exon 2 du gene TREM2 (Triggering receptor expressed on myeloid cells 2) chez des patients tunisiens ayant un TE. Patients et methodes Nous avons sequence l’exon 2 du gene TREM2 dans une cohorte tunisienne de 269 sujets : 111 patients ayant un TE selon les criteres de le nouveau consensus sur la classification des tremblements, recrutes au service de neurologie de l’hopital Razi en Tunisie et 158 temoins. Le tremblement etait considere comme atypique s’il etait asymetrique ou compatible avec un syndrome TE plus. Les donnees epidemiologiques et cliniques ont ete recueillies. Resultats La substitution p.R47H du variant rs75932628 a ete retrouvee chez 2 patients et aucun des temoins avec une association significative avec le TE (pc = 0,048). Le variant p.Thr96Lys (rs2234253) etait le plus frequent chez le malades TE (10 cas) et le seul retrouve chez les temoins (6 cas). Aucune correlation avec les variants rs2234253, rs143332484, rs121908402 et rs200392967 n’a ete observee. Aucune difference n’a ete notee entre les formes typiques et atypiques de TE dans notre cohorte. Discussion Nos resultats suggerent une association de la substitution TREM2 p.R47H au TE dans la population tunisienne. Dans une etude anterieure, ce variant a ete etabli comme facteur de risque du TE uniquement dans la population espagnole, mais pas dans les populations italiennes, allemandes, nord-americaines ou taiwanaises, plaidant en faveur de differences specifiques a la population dans la repartition allelique. Conclusion Nos resultats suggerent un role probablement prejudiciable du TREM2 dans la pathogenese du TE chez les Nord-Africains. D’autres etudes plus larges sont requises pour les confirmer.

HCV has been associated with a pro-inflammatory state, which predisposes to hepatocellular carcinoma (HCC). However, the different molecular mechanisms underlying the effect of HCV infection on HCC progression remain unclear. Although HCV infection illustrates the potential role of host genetics in the outcome of infectious diseases, there is no clear overview of some single nucleotide polymorphisms (SNPs) influencing spontaneous or treatment-induced HCV eradication. We studied the possible role of HCV infection in the processes of HCC initiation and performed a systematic analysis using data mining approaches to identify host polymorphisms associated with treatment response and HCC development using topological analysis of protein-proteins interactions (PPI) networks. On the basis of our analysis performed, we identified key hub proteins related to HCV-treatment response infection and to HCC development. Host genetic polymorphisms, such as inosine triphosphatase (ITPA), interferon, lambda 3 (IFNL3), Q5 interferon, lambda 4 (IFNL4), toll-like receptors (TLRs) and interferon-stimulated gene 15 (ISG-15), were identified as key genes for treatment prediction and HCC evolution. By comparing unique genes for HCV-treatment response and genes particular to HCV-HCC development, we found a common PPI network that may participate in more extensive signalling processes during anti-HCV treatment, which can play important roles in modulating the immune response to the occurrence of HCC. Data mining is an effective tool for identifying potential regulatory pathways involved in treatment response and HCC development. Our study may contribute to a better understanding of HCV immunopathogenesis and highlights the complex role of host genetics in HCV clearance.

Background Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC), a common primary liver malignancy, and the third leading cause of cancer-related death. The HCC risk increases with the severity of liver inflammation, and the clinical course of HCV infection depends on a balance between pro- and anti-inflammatory cytokines. The former includes interleukin (IL)-6, while the latter includes IL-10. However, the exact pathogenic mechanisms underlying IL-6 and IL-10 effects remain unclear. Methods The present study evaluated 174 chronic HCV Tunisian patients. Polymorphisms of IL-6 (rs1880242, rs1474847, rs2069840, rs1800797, rs1800796, rs2069845, rs2069827, rs1474348, rs1800795), and IL-10 (rs1800896, rs1800871, rs1800872, rs1554286, rs1878672, rs1518111) were determined by real-time PCR. Results Notable differences between chronic HCV-infected patients and HCC patients were observed for the three IL-10 SNPs; rs1800871 (−819T/C), rs1800872 (−592A/C), and rs1878672. Carriage of IL-6 rs1800796 G/G genotype, IL-6 rs1474358 C-allele, and IL-6 rs1800797 A-allele was more frequent in chronic HCV-infected patients than in HCC patients. On the other hand, IL-6 rs1474358 GG genotype had a favourable factor for HCC establishment. Conclusion IL-10 and IL-6 SNPs markedly influence the clinical outcomes of HCV infection. These SNPs could be used as biomarkers for early detection and molecular therapy for preventing HCC, and prognostic factors for predicting the clinical outcomes of HCC.

Despite considerable progress in the treatment of chronic hepatitis C, many countries do not have access to these new treatments.Predictive markers of response to treatment are therefore necessary before initiating with historical combination therapy (PEG-IFN+ribavirin) for these populations.We therefore evaluated the influence of IL28B polymorphisms on treatment response and Inosine Triphosphate (ITPA) polymorphisms on the incidence of anaemia in a population of 120 Tunisian patients infected with HCV genotype 1b and treated.The frequencies of favourable IL28B genotypes were 47% (CC for rs12979860) and 63% (TT for rs8099117). Patients in whom favourable IL28B alleles were identified had a higher chance of successful therapy: 82% for CC (rs12979860) and 75% for TT (rs8099117). Viral load decline during the first twelve weeks of treatment was more pronounced in patients with a favourable genotype (p0.0001). For patients with an unfavourable genotype, the second phase of viral decline was more pronounced in patients with SVR. A viral load decline cut-off of 2.68logIU/mL at week 12 was best suited to discriminate responders from non-responders with an odds ratio of 40 (95% CI:11.53-170.3). Analysis of ITPA polymorphisms revealed that 16% of Tunisian patients presented ITPase deficiency. None of these patients experienced a decline of ribavirin doses during treatment versus 67% for patients without ITPase deficiency (p0.001).These data obtained in a Tunisian population should optimize before and during treatment the chances of success for treatments currently available in Tunisia for chronic HCV infection.

Our study aimed to evaluate the association between IL-1α (4845 G/T), IL-1β (-511C/T) and IL-1RN (VNTR) polymorphisms and risk of cervical cancer. This case-control study investigates three polymorphisms in 130 patients and 260 controls by PCR-restriction fragment length polymorphism (RFLP). The IL-1RN (VNTR) A1/A3 genotype appear as a cervical cancer risk factor (p = 0.048; OR = 2.92; 95 % CI = 1.00-8.74), moreover, the L/2* decreased the risk (p = 0.011; OR = 0.47; 95 % CI = 0.25-0.88) and may be a protective factor against this pathology. Stratified analysis according to the FIGO stage subgroup revealed that the IL-1β-511 T/T genotype and T allele may be a protective factors against cervical cancer development for patients with early stage (p = 0.030; OR = 0.46; 95 % CI = 0.22-0.96) (p = 0.020; OR = 0.68; 95 % CI = 0.48-0.97). However, for the patients with advanced FIGO stage, IL-1RN-VNTR L/2* genotype appear as a protective factor for this pathology (p = 0.023; OR = 0.29; 95 % CI = 0.08-0.99). The (G-T-L) haplotype showed a significant decreased frequency in cervical cancer patients as compared to controls (p = 0.032; OR = 0.53; 95 % CI = 0.29-0.95). In contrast, the (T-T-2*) combination appear a risk factor for the development of cervical cancer (p = 0.018; OR = 1.57; 95 % CI = 1.07-2.30). Our study suggested that IL1 cluster polymorphisms and haplotypes may be a genetic risk factor for cervical cancer.

Objective. The aim of this study was to investigate the role of IL10-1082 and IFN-γ+874 polymorphisms in susceptibility to cervical cancer among Tunisian women. Study Design. The IL10-1082 and IFN-γ+874 polymorphisms were analyzed by ARMS-PCR in 160 healthy women and 122 with cervical cancer. The search for associations between those polymorphisms and cervical cancer was based on the χ2 test or Fisher's exact test. Results. The IFN-γ+874 polymorphism showed significant increased frequency of T allele in healthy controls compared with patients (OR = 0.71, 95% CI = 0.50–1.01, and P=0.0459) and individuals with homozygote IFN-γ+874 T/T genotype were at lesser risk of cervical cancer (OR = 0.53, 95% CI = 0.31–0.92, and P=0.015). However, carriers of allele have higher risk for developing cervical cancer (OR = 1.88, 95% CI = 1.09–3.24, and P=0.015). At the polymorphic nucleotide in position 1082 of the IL10 promoter, no differences were found between patients and controls subjects. Conclusion. Our study shows that the T/T genotype polymorphism of IFN-γ+874 T>A is a protective factor for cervical cancer among Tunisian women.