Mahdia, Tunisia
Mahdia, Tunisia

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PubMed | CHU Tahar Sfar, Pharmacology and Experimental Physiology Laboratory, Molecular Endocrinology Laboratory, University of Monastir and University of Sousse
Type: Journal Article | Journal: Gene | Year: 2015

The FTO (fat mass and obesity associated) gene was associated with different metabolic disorders in populations from different origins but with great difference between African and non-African populations. North-African populations combine many genetic backgrounds, among which African, Berber and Caucasian components, which makes North-Africans a good model for studying the genetic association of FTO. In the present investigation we explored the association of FTO gene with polycystic ovary syndrome (PCOS) in a population from Tunisia (n=278). Single nucleotide polymorphisms (SNPs) used in this study were previously associated in non-African populations: rs8050136 (A/C), rs9939609 (A/T), rs9930506 (G/A), or in both African and non-African populations: rs8057044 (A/G). Genotyping was performed by allelic discrimination method on StepOne real-time PCR system or KASPar technology. Linkage disequilibrium (LD) pattern was assessed by HAPLOVIEW and reconstruction of haplotypes was performed by PHASE, while statistical analyses were performed using StatView and GoldenHelix programs. Among the 13 haplotypes in the population, three (h1, h7 and h13) were strongly associated with PCOS notably h13 (P<0.0001, OR95%CI=0.040 [0.005-0.294]) while SNPs display weaker association. Moreover the LD pattern in FTO in the Tunisian population (r(2) index) was intermediary between those of Caucasian and Africans. This highlights the need for studying the genetics of complex disorders in the North-African populations taking into-account the haplotype structure of candidate loci more than SNPs taken alone.


Ben-Salem A.,University of Monastir | Ajina M.,University of Sousse | Suissi M.,CHU Tahar Sfar | Daher H.S.,Arabian Gulf University | And 2 more authors.
Gene | Year: 2014

Background and aims: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women in their child-bearing age, and is often associated with insulin resistance and type 2 diabetes (T2DM). Given the overlap between PCOS and T2DM, we investigated the association of transcription factor-7-like 2 (TCF7L2) variants rs4506565, rs7903146, rs12243326, and rs12255372 with the susceptibility to PCOS. Subjects and methods: Study subjects comprised 119 Tunisian women with PCOS (mean age 29.8. ±. 4.7. years), and 150 control women (mean age 30.6. ±. 5.9. years). TCF7L2 genotyping was done by the allelic discrimination/real-time PCR method. Results: Minor allele frequencies (MAFs) of rs4506565 (P= 0.61), rs7903146 (P= 0.68), rs12243326 (P= 0.56), and rs12255372 (P= 0.60) were comparable between PCOS cases and control subjects. As the four tested TCF7L2 variants were in linkage disequilibrium, 4-locus (rs4506565, rs7903146, rs12243326, rs12255372) haplotype analysis demonstrated that haplotype 2111 was initially negatively associated with PCOS [. P= 0.035; OR (95% CI). = 0.13 (0.02-0.85)], which was later lost upon correcting for multiple comparisons [. Pc= 0.248]. Conclusion: Our data suggest that there is weak or no contribution of TCF7L2 gene polymorphism to PCOS in Tunisian women. Further studies with larger samples are necessary to confirm this observation. © 2013 Elsevier B.V.


Lakhdar R.,Biochemistry and Molecular Biology Laboratory | Denden S.,Biochemistry and Molecular Biology Laboratory | Knani J.,CHU Tahar Sfar | Leban N.,Biochemistry and Molecular Biology Laboratory | And 5 more authors.
Genetics and Molecular Research | Year: 2010

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease with possible genetic predisposition and involve-ment of various environmental factors. Several candidate genes have been reported as potentially associated with this lung disease. The glu-tathione S-transferase P1 gene (GSTP1) was proposed to be involved in susceptibility to develop COPD. It belongs to the GST family, which is a group of phase II enzymes that catalyze the glutathione conjugation of many endogenous and exogenous electrophilic compounds, such as car-cinogens, therapeutic drugs, environmental toxins, and oxidative stress products. We conducted a case-control study to investigate genetic poly-morphisms of this enzyme [exon 5 (Ile105Val) and exon 6 (Ala114Val)] in 234 unrelated COPD cases and 182 healthy controls from a Tunisian population. Genotyping was carried out using polymerase chain reaction and restriction fragment length polymorphism methods. GSTP1 Ala114/Val114 and Val114/Val114 genotypes were not found in either patients or healthy controls. However, there were differences in the distribution of various exon 5 GSTP1 genotypes between COPD patients and healthy controls. GSTP1 Val105/Val105 was significantly more com-mon in patients compared to controls (OR = 2.67; 95%CI = 1.45-4.92; P = 0.0013). Multivariate logistic regression analysis confirmed a signifi-cant relationship between the mutant genotype and COPD (OR = 2.58; 95%CI = 1.31-5.09; P = 0.026), after adjustment for classic risk factors. Analysis of variance showed no correlation between age, body-mass in-dex, pack-years, percentage of predicted FEV1 values, and any of the GSTP1 genotypes. We conclude that subjects with GSTP1 Val105 allele are at higher risk of COPD.


Lakhdar R.,Biochemistry and Molecular Biology Laboratory | Denden S.,Biochemistry and Molecular Biology Laboratory | Knani J.,CHU Tahar Sfar | Leban N.,Biochemistry and Molecular Biology Laboratory | And 5 more authors.
Disease Markers | Year: 2011

Smoking is considered as the major causal factor of chronic obstructive pulmonary disease (COPD). Nevertheless, a minority of chronic heavy cigarette smokers develops COPD. This suggests important contribution of other factors such as genetic predisposing. Our objective was to investigate combined role of EPHX1, GSTP1, M1 and T1 gene polymorphisms in COPD risk, its phenotypes and lung function impairment. Prevalence of EPHX1, GSTP1, M1 and T1 gene polymorphisms were assessed in 234 COPD patients and 182 healthy controls from Tunisia. Genotypes of EPHX1 (Tyr113His; His139Arg) and GSTP1 (Ile105Val; Ala114Val) polymorphisms were performed by PCR-RFLP, while the deletion in GSTM1 and GSTT1 genes was determined using multiplex PCR. Analysis of combinations showed a significant association of 113His/His EPHX1/null-GSTM1 (OR=4.07) and null-GSTM1/105Val/Val GSTP1 (OR =3.56) genotypes with increased risk of COPD (respectively P=0.0094 and P=0.0153). The null-GSTM1/ null-GSTT1, 105Val/Val GSTP1/null GSTT1, 113His/His EPHX1/null-GSTM1 and null-GSTM1/105Val/Val GSTP1 genotypes were related to emphysema (respectively P=0.01; P=0.009; P=0.008 and P=0.001). Combination of 113His/His EPHX1/null-GSTM1 genotypes showed a significant association with the decrease of Δ FEV1 in patients (P =0.028). In conclusion, our results suggest combined EPHX1, GSTP1, GSTM1 and GSTT1 genetic polymorphisms may play a significant role in the development of COPD, emphysema and decline of the lung function. © 2011 - IOS Press and the authors. All rights reserved.


Kerkeni M.,University of Monastir | Saidi A.,University of Monastir | Bouzidi H.,CHU Tahar Sfar | Yahya S.B.,CHU Fattouma Bouguiba | Hammami M.,University of Monastir
Microvascular Research | Year: 2012

Objectives: The advanced glycation end products (AGEs)-receptor for AGE (RAGE) axis activity are implicated in diabetic vascular complications. We measured serum AGE, sRAGE and pentosidine levels in Tunisian patients with diabetic retinopathy (DR) and examined whether these biomarkers are related to the severity of DR. Design and methods: We included 30 healthy control subjects and 100 diabetic patients were divided into 2 subgroups: 40 patients with nonproliferative diabetic retinopathy (NPDR), and 60 patients with proliferative diabetic retinopathy (PRD). AGEs, sRAGE and pentosidine were measured in serum by ELISA. Results: Serum levels of AGEs, sRAGE and pentosidine were significantly increased in patients with diabetes mellitus compared to nondiabetic controls (P<.01, P<.001, P<.001 respectively). In diabetic patients, serum AGEs, sRAGE and pentosidine levels were significantly higher in patients who had PDR than in those with NPDR (P=.001, P=.01, P=.005 respectively). Furthermore, in stepwise multivariate regression analysis, the levels of pentosidine and duration of diabetes were independently associated with severity of DR. Conclusion: Serum AGEs, sRAGE, and pentosidine levels are related with the presence of DR. Duration of diabetes and pentosidine were independently correlated with the severity of DR. © 2012 Elsevier Inc.


Lakhdar R.,University of Monastir | Denden S.,University of Monastir | Knani J.,CHU Tahar Sfar | Leban N.,University of Monastir | And 5 more authors.
Biochemical Genetics | Year: 2010

GSTM1 and GSTT1 polymorphisms have been proposed in relationship with chronic obstructive pulmonary disease (COPD). We investigated the association between these polymorphisms and COPD (as well as its subtypes emphysema and chronic bronchitis) in 234 COPD patients and 182 healthy controls in the Tunisian population. Genotyping was performed using multiplex PCR. GSTM1-null genotype frequency was significantly higher in COPD patients than in controls (P = 0.02); however, multivariate analysis of cofounding variables showed no independent association with this genotype (P = 0.073). In contrast, the association of the GSTM1-null genotype with emphysema was significant, even after adjustment for risk factors (P = 0.011). There were no significant differences in GSTT1 genotypes between patients and controls. The GSTM1 null allele is likely not an independent risk factor for COPD but is related to emphysema, whereas the GSTT1 gene is not associated with the disease. © 2010 Springer Science+Business Media, LLC.


Lakhdar R.,Biochemistry and Molecular Biology Laboratory | Denden S.,Biochemistry and Molecular Biology Laboratory | Mouhamed M.H.,Biochemistry Laboratory | Chalgoum A.,Biochemistry Laboratory | And 6 more authors.
Experimental Lung Research | Year: 2011

This study was undertaken to ascertain if a relationship existed between oxidative status and polymorphisms of microsomal epoxide hydrolase X1 (EPHX1), glutathione S-transferase P1 (GSTP1), GSTM1, and GSTT1 in chronic obstructive pulmonary disease (COPD). Erythrocyte glutathione peroxidase (GSH-px), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and plasma GST activities and total antioxidant status (TAS) as antioxidative stress markers were determined and compared either with individual and combined genotypes of EPHX1 exon 3, GSTP1 exon 5, GSTM1, and GSTT1 polymorphisms in COPD patients and healthy controls from the central area of Tunisia. Statistical data processing revealed significantly lower GSH-px, GR, SOD, CAT, GST, and TAS values in COPD patients in comparison to the control group (P <.001). As for genotypes, there was a no significant association in each of the 6 parameters and individual genotypes (P >.05). A significant correlation between the studied parameters and combined null GSTM1/null GSTT1 (GSH-px: P <.001, GR: P =.026, CAT: P =.018, GST: P =.022, TAS: P =.046), His113His EPHX1/null GSTM1 (GSH-px: P =.001, GST: P =.0012, TAS: P =.013), His113His EPHX1/Val105Val GSTP1 (GSH-px: P =.048, CAT: P =.026, GST: P =.031), and null GSTM1/Val105Val GSTP1 (GSH-px: P =.011, GR: P =.0028, GST: P =.0054, TAS: P =.032) was found in patients. In conclusion, combined genetic polymorphisms of GSTM1, GSTT1, GSTP1, and EPHX1 may have favorable effects on redox balance in COPD patients. © 2011 Informa Healthcare USA, Inc.


Kerkeni M.,University of Monastir | Saidi A.,University of Monastir | Bouzidi H.,CHU Tahar Sfar | Letaief A.,CHU Fattouma Bouguiba | And 2 more authors.
Diabetes and Vascular Disease Research | Year: 2013

Serum soluble receptor for advanced glycation end product (sRAGE) may reflect the activity of the advanced glycation end product (AGE)-receptor for advanced glycation end product (RAGE) axis, which has been proposed as a potential mechanism linking hyperglycaemia to vascular complications in diabetes. We have investigated whether serum AGEs, sRAGE and pentosidine levels were increased and correlated with microvascular complications in type 2 diabetes mellitus (DM). We included 30 healthy control subjects, and 200 diabetic patients were divided into two subgroups: 100 patients with diabetic retinopathy and 100 patients with diabetic nephropathy. AGEs, sRAGE and pentosidine were measured in serum by enzyme-linked immunosorbent assay (ELISA). Serum AGEs, sRAGE and pentosidine levels were significantly increased in diabetic patients with retinopathy and in diabetic patients with nephropathy compared to control subjects (p < 0.001). Serum AGEs, sRAGE and pentosidine levels are positively associated with microvascular complications in type 2 DM. Multiple regression analysis reveals serum pentosidine as an independent determinant of the presence of diabetic retinopathy (p = 0.004) and the presence of hypertension (p = 0.018) and hyperlipidaemia (p = 0.036). Pentosidine levels may be a biomarker for microvascular complications in type 2 diabetic patients. © The Author(s) 2012.


Denden S.,Biochemistry and Molecular Biology Laboratory | Denden S.,Tunis el Manar University | Lakhdar R.,Biochemistry and Molecular Biology Laboratory | Boudawara Keskes N.,CHU Tahar Sfar | And 3 more authors.
Biochemical Genetics | Year: 2013

It is generally agreed that the protease inhibitor (PI) alleles PI S (Val264Glu) and PI Z (Lys342Glu) are the most common alpha 1 antitrypsin deficiency variants worldwide, but the PI Mmalton allele (ΔPhe52) prevails over these variants in some Mediterranean regions. In eastern Tunisia (Mahdia), we screened 100 subjects with chronic obstructive pulmonary disease for these variants. The PI S and PI Z alleles were genotyped by the previously described SexAI/Hpγ99I RFLP-PCR. We provide here a new method for PI Mmalton genotyping using mismatched RFLP-PCR. These methods are suitable for routine clinical application and can easily be reproduced by several laboratories, since they do not require extensive optimization, unlike the previously described bidirectional allele-specific amplification PCR for PI Mmalton genotyping. Our results were in agreement with previous reports from central Tunisia (Kairouan), suggesting that the PI Mmalton mutation is the most frequent alpha 1 antitrypsin deficiency-related mutation in Tunisia. © 2013 Springer Science+Business Media New York.


Lakhdar R.,Biochemistry and Molecular Biology Laboratory | Denden S.,Biochemistry and Molecular Biology Laboratory | Knani J.,CHU Tahar Sfar | Leban N.,Biochemistry and Molecular Biology Laboratory | And 5 more authors.
Genetic Testing and Molecular Biomarkers | Year: 2010

It is well known that cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only 10%-20% of chronic heavy cigarette smokers develop symptomatic disease, which suggests the presence of genetic susceptibility. Microsomal epoxide hydrolase (EPHX1) is an enzyme involved in the protective mechanism against oxidative stress. It has been reported that gene polymorphisms of this enzyme may be associated with variations in EPHX1 activity. In this study, we aimed at investigating the relationship between EPHX1 polymorphisms and susceptibility to COPD in the Tunisian population. EPHX1 exon 3 (rs1051740, Tyr113His) and exon 4 (rs2234922, His139Arg) polymorphisms were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analysis. These techniques were used to examine a total of 416 Tunisian individuals, including 182 blood donors and a group of 234 COPD patients. All subjects were not related. An increased risk for COPD was observed in subjects with EPHX1 His113-His113 genotype (odds ratio=2.168; confidence interval 1.098-4.283; p=0.02386). However, multivariate logistic regression analysis showed no significant relationship between the mutant genotype and the disease after adjustment for sex, age, body mass index, smoking status, and pack-year smoking (odds ratio=1.524; confidence interval, 0.991-6.058; p=0.06137). Regarding the two subtypes of COPD, our investigations demonstrated that there is no significant correlation between exon 3 polymorphism and the chronic bronchitis subgroup (p=0.09034). The relation between exon 3 polymorphism and emphysema was significant in the univariate analysis (p=0.02257), but no association was found after controlling for classic risk factors (p=0.06273). In conclusion, our results showed that there is a weak relation between 113His genotype and COPD, and no apparent relation between 139Arg and COPD in the studied Tunisian population. © 2010, Mary Ann Liebert, Inc.

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