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Background: Fibroblast growth factor (FGF) 1 and FGF2 were previously linked with preeclampsia (PE), possibly through altering decidual and placental FGFR2 expression. Since common variation in FGF1 and FGF2 might influence FGF1 and FGF2 activity, this study evaluated whether common FGF1 and FGF2 variants are linked with PE and associated features.Methods: The association between FGF1 rs34011 and FGF2 rs2922979 SNPs and PE were tested in 300 women with PE, and 300 age-matched control women.Results: The allelic distribution of FGF1 rs34011 (P < 0.001) but not FGF2 rs2922979, variants were significantly different between PE cases and control women. Marginal association of FGF2 rs2922979 was seen after controlling for key covariates. Setting homozygous major allele genotype (1/1) as reference, significantly higher frequencies of heterozygous rs345011, and reduced frequency of heterozygous rs2922979 genotype carriers were seen in PE cases; the distribution of the remaining genotypes were comparable between cases and controls. Carriage of rs2922979 minor allele correlated with fasting glucose (P = 0.02), while the presence of rs34011 minor allele was not correlated with PE-associated features.Conclusions: Our study suggests that the genetic variants of FGF1 rs34011, more so than FGF2 rs2922979, may play a role in PE pathogenesis in Tunisian women. These findings need confirmation in other ethnic populations. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies and replication analyses have linked chromosome 18q21.1–23 with type 2 diabetes (T2DM) and its complications, including diabetic nephropathy (DN). Here we investigated the association of POL1-nearby variant rs488846, MALT1-nearby variant rs2874116, MC4R-nearby variant rs1942872, PHLPP rs9958800 and DSEL-nearby variant rs9966483 single nucleotide polymorphisms (SNPs) in the 18q region, previously linked with DN in African-Americans, with T2DM in (North African) Tunisian subjects, followed by their association with DN, which was performed subsequent to the analysis of the association with T2DM. Study subjects comprised 900 T2DM cases and 748 normoglycemic control, and genotyping was carried out by PCR–RFLP analysis. Of the 5 SNPs analyzed, POL1-nearby variant rs488846 [P =0.044], and MC4R-nearby variant rs1942872 [P =0.012] were associated with moderate risk of T2DM. However, there was a lack of consistency in the association of the 5 tested SNPs with DN. As such, it appears that the three chromosome 18q region variants appear to play a role in T2DM pathogenesis, but not with DN in North African Tunisian Arabs. [Copyright &y& Elsevier]

Highlights: [•] DMH promotes erythrocyte oxidative damage and haematological alterations. [•] TQ pre-treatment repairs these DMH-induced alterations and prevents tumour. [•] TQ post-treatment exerts a slight effect. [•] TQ is effective in DMH-cancer via its prevention of erythrocyte oxidative stress. [Copyright &y& Elsevier]

A relationship between apolipoprotein E (Apo E) genotype and stroke was previously suggested, but with inconsistent results. We investigated the relationships among serum lipid levels, Apo E alleles and genotypes, and stroke risk factors in 216 stroke patients and 282 age- and sex-matched controls. Fasting blood samples were collected for total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride level determination and for genomic DNA extraction. Apo ϵ was genotyped by polymerase chain reaction–restriction fragment length polymorphism (Cfo I) analysis. Increasing levels of total cholesterol, LDL-C, HDL-C, and triglycerides were associated with elevated stroke risk and was more pronounced in Apo E4-carrying subjects than in E3- and/or E2-carrying subjects. Apo ϵ3 was significantly lower (0.546 vs 0.736; P < .001), whereas Apo ϵ4 was higher in the stroke patients (0.370 vs 0.181; P < .001); Apo ϵ2 was present at low but comparable frequencies. The prevalence of E3/E3 was lower and that of E4-containing phenotypes (E3/E4 and homozygous E4/E4) was higher in the stroke patients. The prevalence of the E4-containing phenotypes were significantly higher in ischemic versus hemorrhagic (P < .001) and in small-vessel versus large-vessel stroke cases (P < .001), and was associated with increased need for statin drugs (P = .040). Logistic regression models, after adjusting for potentially confounding variables including lipid profile, age, and sex, showed an significant association of apo ϵ4 genotype with risk of stroke (P = .033). Our findings indicate that Apo ϵ4 is an independent risk factor associated with an altered lipid profile in this study population. [Copyright &y& Elsevier]

Mutations in the plasminogen activator inhibitor-1 (PAI-1) gene, along with altered PAI-1 and tissue-type plasminogen activator (tPA) levels, have been implicated in stroke pathogenesis. We investigated the association of PAI-1 and tPA levels with stroke as a function of PAI-1 4G/5G and -844G/A genotypes, as well as the link between these PAI-1 gene variants and stroke risk, in a case-control study of 135 ischemic stroke patient, diagnosed according to clinical and radiologic findings and confirmed by computed tomography scan. Controls (n = 118) were age- and sex-matched and had no personal/family history of stroke. PAI-1 4G/5G and -844G/A genotyping were done by polymerase chain reaction–restriction fragment length polymorphism, and PAI-1 and tPA levels were measured by enzyme immunoassay. Significant elevation in PAI-1 and marked reduction in tPA levels were seen in stroke patients and were correlated with 4G/5G, but not with -844G/A, PAI-1 variants. Whereas the frequencies of 4G or -844A alleles were comparable between patients and controls, 4G/4G carriers had reduced risk of stroke compared with other genotypes (odds ratio [OR] = 0.54; 95% confidence interval [CI] = 0.31-0.95). The 4G/-844A haplotype also was more closely associated with reduced stroke risk (OR = 0.43; 95% CI = 0.20-0.97) than 5G/-844A or 4G/-844G haplotypes. Regression analysis demonstrated that 4G homozygosity (OR = 0.176), hypertension (OR = 6.288), and body mass index (OR = 1.325) were independent predictors of stroke. The protective effect of 4G allele against stroke suggests involvement of PAI-1 4G/5G polymorphism in stroke through a mechanism not related to fibrinolysis, possibly involving altered plaque stabilization, and/or through antagonism of tPA effects. [Copyright &y& Elsevier]

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Abstract 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. Highlights • LEP gene variants association with PCOS depends on ethnic/racial background of study subjects. • None of the tested LEP variants was linked with altered leptin serum concentrations. • Positively and negatively PCOS-associated LEP haplotypes were seen in Bahraini women. • No LEP haplotype associated with PCOS was identified in Tunisians. [ABSTRACT FROM AUTHOR]

Background and aim Colorectal cancer (CRC) is a worldwide leading cause of mortality. Genetic studies have associated single nucleotide polymorphisms in genes encoding microRNAs with CRC risk but results are mostly inconclusive across variable ethnicities. In this study, we investigated the association of hsa-mir-149 rs2292832 C/T, hsa-mir-146a rs2910164 G/C and hsa-mir-196a2 rs11614913 C/T and explored their roles in clinicopathological features of CRC progression in an Eastern Tunisian cohort. Subjects and methods Three hundred thirteen subjects were enrolled in our retrospective study including 152 CRC cases and 161 controls. Genotyping was assayed by RFLP-PCR (Restriction Fragment Length Polymorphism-Polymerase Chain Reaction) method. SPSS v.18.0, R and SNP Stats online software performed statistical analysis. Results Significantly higher hsa-mir-149 C/T rs2292832 minor allele frequency was associated with increased risk of CRC [ p  = .03; OR = 1.54 (1.08–2.19)]. In addition, significant crude associations of hsa-mir-149 C/T rs2292832 polymorphism were detected under codominant, dominant and additive models of inheritance. After adjusting for covariates and performing FDR correction, these associations did not remain. No associations were detected for hsa-mir-146a G/C rs2910164 and hsa-mir-196a2 C/T rs11614913. When performing stratified analysis of clinicopathological features according to genotypes, a significant association ( p  = .004) was found between hsa-mir-146a G/C rs2910164 and tumour differentiation grade. Regression analysis according to CRC progression features had demonstrated a trend toward significance in overdominant model of inheritance for hsa-mir-149 C/T rs2292832 with a protective effect [ p  = .05; OR = 0.51 (0.26–1.02)]. Conclusion Hsa-mir-149 C/T rs2292832 and hsa-mir-146a G/C rs2910164 may influence CRC risk in an ethnicity-dependent manner by interfering with CRC progression parameters in Tunisian cohort. [ABSTRACT FROM AUTHOR]

Background Estrogen is key to breast cancer pathogenesis, and acts by binding its receptor (ER), which exists as ERα and ERβ, encoded by ESR1 and ESR2 genes, respectively. Studies that investigated the association of ESR1 and ESR2 variants with breast cancer yielded mixed outcome, and ethnic contribution was proposed. We evaluated the association between ESR1 and ESR2 variants and breast cancer and associated features in Tunisian women. Methods Retrospective case-control study involving 207 female breast cancer patients, and 284 control women. Genotyping was done by real-time PCR. Results Minor allele frequencies (MAF) of tagging SNPs rs2234693 and rs3798577 ( ESR1 ) were significantly higher, while MAF of rs1256049 ( ESR2 ) was significantly lower in breast cancer patients vs . controls. Patients carrying rs3798577 genotypes had higher risk, while rs1256049 genotype carriers had reduced risk of breast cancer. The association of ESR1 and ESR2 gene variants with breast cancer depended on ER and Her-2 status. ESR1 rs3798577 and ESR2 rs1256049 were associated with breast cancer in ER-positive cases, and ESR1 rs2234693, and rs3798577 were associated with breast cancer in Her-2-negative cases, while the association of ESR2 rs1256049 with breast cancer was seen in Her-2 positive cases. Haploview analysis identified 4-locus ESR1 haplotypes that were positively (CGTT, TACC, and TACT), and negatively (CGTC) associated with breast cancer. No ESR2 haplotypes associated with breast cancer were identified. Conclusion ESR1 alleles and genotypes, and specific 3-locus ESR1 haplotypes are related with increased breast cancer susceptibility in Tunisian women. However, ESR2 variant and specific 1-locus ESR1 haplotype have a protective effect. [ABSTRACT FROM AUTHOR]

Background and aim Polycystic ovary syndrome (PCOS) is a common endocrine disorder, and results from interaction between modifiable and non-modifiable factors, including genetic predisposition. Previous genome-wide association studies and meta-analysis identified DENND1A as PCOS susceptibility locus in some, but not all populations. We investigated whether the association of DENND1A gene variants with PCOS was similar between Tunisian and Bahraini Arab women. Subjects and methods This was retrospective case-control study. Study subjects comprised 320 women with PCOS, and 446 age-and ethnically-matched control women. Genotyping of DENND1A rs10818854, rs2479106, and rs10986105 variants was done by real-time PCR. Results Minor allele frequency of rs10818854 and rs10986105 DENND1A variants were significantly higher among women with PCOS. Setting homozygous wild-type genotype carrier as reference, rs10818854 and rs10986105 were associated with increased risk of PCOS, which persisted after controlling for key covariates, while reduced PCOS risk was seen with only rs2479106 under the additive model. This assigned PCOS susceptibility and protective nature to these genotypes, respectively. Both rs10818854 and rs10986105 were positively associated with HOMA-IR and AMH in women with PCOS. Haploview analysis revealed limited linkage disequilibrium between the tested DENND1A variants. Extensive diversity in haplotypes assignment was seen, with most haplotypes (99.5%) captured by 5 haplotypes. Taking GAT haplotype as reference, AAG, and GAG haplotypes were positively, while GAT haplotype was negatively associated with PCOS. Conclusion The association of DENND1A rs10818854 and rs10986105 variants with PCOS in Tunisian but not Bahraini women confirms the dependence of this association on the ethnic/racial origin of study subjects. [ABSTRACT FROM AUTHOR]

We investigated the association of endothelial nitric oxide synthase ( NOS3 ) polymorphisms − 786T>C, 27-bp repeat 4b/4a, and Glu298Asp with preeclampsia (PE). This was a case–control study involving 345 unrelated Tunisian women with PE and 289 unrelated age- and ethnically matched control women. The − 786C allele was significantly increased in PA patients when compared to healthy controls ( P = 0.015). In contrast, MAF of Glu298Asp ( P = 0.103) and 4b/4a ( P = 0.168) were not significantly different between the study groups. Higher frequencies of heterozygous Glu298/298Asp and homozygous − 786T/− 786T genotypes were seen in PE cases compared to healthy subjects. The combination of genotypes 221 (− 786T>C, Glu298Asp, 4a/4a) was more in PE cases compared with control women (17.68% vs. 8.36%; P = 0.029). Multivariate regression analysis confirmed this association. Genetic variation at the NOS3 locus represents a genetic risk factor for increased susceptibility to PE. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• The G allele at miR146a rs2910164 may serve as protective marker for ALL. • miR-146a rs2910164 genotypes are associated with decreased risk of ALL. • T allele at miR-149 rs2292832 is associated with increased risk of ALL. • miR-149 rs2292832 genotypes exhibits a higher risk of developing ALL. MicroRNAs (miRNAs) are promising biomarkers of hematological malignancies, including acute lymphoblastic leukaemia (ALL). Recent studies revealed that miRNA single nucleotide polymorphisms (miR-SNP) modulate cancer risk by regulating various signaling pathways. However, their association with altered risk of ALL yielded inconsistent results. This study aims to investigate the association of four miR-SNPs with altered risk of ALL risk in Tunisian, the first on North African population. A retrospective case-control study exploring the association of miR-146a , miR-196a2 , miR-499 , and miR-149 SNPs in 126 ALL patients and 126 healthy controls. Of the tested variants, significantly lower minor allele frequencies (MAF) of miR-146a C-allele and higher MAF frequency of miR-149 T-allele (P = 0.006) were seen in ALL cases. The association of miR-149 rs2292832 (Pc = 0.02), but not miR-146a rs2910164 (Pc = 0.11) persisted after correcting for multiple comparisons. Significantly reduced prevalence of miR-146a G/C genotype and higher frequency of miR-149 C/T genotype were seen in ALL cases vs. control subjects, which translated into negative association of miR-146a (rs2910164) with ALL according to the codominant and dominant models. Similarly, miR-149 (rs2292832) was positively associated with ALL according to the codominant and dominant genetic models. Three combinations comprising miR-146a / miR-196a2 GG vs CT + TT genotype combination, miR-146a / miR-499 GG vs TC + CC genotype combination, and miR-146a / miR-149 GG vs CT + TT genotype combination, were less frequent in ALL patients than in controls, and were negatively associated with the presence of ALL. Our study suggests that miR-146a and miR-149 polymorphisms constitute biomarkers for personalized diagnosis of ALL. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated pre- and post-thymoquinone (TQ) treatment on 1,2-dimethyl-hydrazine (DMH)-induced oxidative stress during initiation and promotion of colon carcinogenesis. Wistar rats were induced with DMH (20mg/kg) for 10 or 20weeks, and treated with TQ (5mg/kg). Following sacrifice, the colons were analysed for tumour development, reactive oxygen species (ROS) generation, lipid peroxidation [conjugated diene (CD) and malondialdehyde (MDA)], antioxidants [glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH)], and histological changes. Increased ROS levels and lipid peroxidation were seen during tumour initiation and promotion. All ROS-scavenging enzyme activities were increased upon shorter DMH treatment but not following longer treatment, while GSH amount was increased upon both treatments. Oxidative state perturbations were associated with moderate colon dysplasia and 30% tumour incidence at initiation and marked dysplasia and 100% tumour incidence at promotion. TQ pre-treatment restored completely DMH-induced oxidative stress at initiation and established histological changes and tumour development. It also abrogated oxidative status aggravation at promotion, and significantly reduced tumour incidence (67%). By comparison, TQ post-treatment corrected oxidative status and attenuated tumour development at initiation. It slightly reduced MDA and antioxidant level at promotion, with a slight reduction in tumour state and dysplasia degree. TQ is efficacious in protecting and curing DMH-induced initiation phase of colon cancer, while exerting a protective role at promotion. TQ effect seems to be related to its capacity in preventing DMH-induced oxidative stress. These in vivo results support the notion that TQ may be of value as a chemo-preventive alternative in colorectal cancer patients. [Copyright &y& Elsevier]

Abstract: Genome-wide association studies validated transcription factor 7-like 2 (TCF7L2) gene as confirmed type 2 diabetes (T2DM) susceptibility locus, and an ethnic contribution of TCF7L2 variants to T2DM risk was indicated. The aim of this study was to replicate in a Tunisian Arab population identified associations of common TCF7L2 variants with T2DM. We tested the association of TCF7L2 variants: rs4506565, rs7903146, rs12243326, and rs12255372, with T2DM in 900 Tunisian patients and 875 control subjects. TCF7L2 genotyping was done by allelic discrimination/real-time PCR method. Minor allele frequencies of rs4506565 (P =2.4×10−8), rs7903146 (P =1.2×10−6), rs12243326 (P =8.4×10−8) and rs12255372 (P =1.1×10−5) were significantly higher in cases. The four tested TCF7L2 variants were in linkage disequilibrium, and 4-locus (rs4506565, rs7903146, rs12243326, rs12255372) haplotype analysis demonstrated that haplotype 1111 was negatively associated (Pc <0.001), while haplotypes 2222 (Pc =0.008) and 2211 (Pc =0.020) were positively associated with T2DM risk, after controlling for a number of covariates. The strong contribution of TCF7L2 gene variants to T2DM among Tunisians is in line with similar findings in other ethnic groups, confirming TCF7L2 as a common T2DM candidate gene. [Copyright &y& Elsevier]

Abstract: Aims: Polymorphisms of KCNQ1 were previously associated with type 2 diabetes (T2DM) in select Caucasian and non-Caucasian populations. We investigated the association of rs231361, rs231359, rs151290, rs2237892, rs2283228, rs2237895, and rs2237896 KCNQ1 polymorphisms with T2DM in Tunisian Arabs. Subjects and methods: Subjects comprised 900 T2DM patients and 600 normoglycemic controls. KCNQ1 genotyping was done by allelic discrimination (real-time PCR) and PCR-RFLP methods; the contribution of KCNQ1 polymorphisms to T2DM were analyzed by Haploview and regression analysis. Results: Minor allele frequency (MAF) of the 7 tested KCNQ1 variants was comparable between T2DM cases and controls. Mild association of rs2237892 genotypes with T2DM was seen (P =0.014), highlighted by the significant association of the C/T genotype with increased T2DM risk (OR, 2.11; 95%CI, 1.25–3.53), after adjusting for BMI, gender, systolic and diastolic blood pressure, and serum lipid profile. Heterogeneity in linkage disequilibrium pattern between tested KCNQ1 variants analyzed was seen. Two-locus (rs231361 and rs231359) and 5-locus (remaining 5 SNPs) haplotype analysis did not reveal any significant association with any of the haplotypes contained in either block 1 or block 2. Conclusion: These results indicate that there was no evidence for an association of KCNQ1 polymorphisms with T2DM in Tunisian Arabs. [Copyright &y& Elsevier]

Abstract: Adiponectin is an adipocyte-produced protein involved in regulating glucose, lipid, and energy metabolism, and is encoded by ADIPOQ (APM1) gene. ADIPOQ polymorphisms were previously associated with type 2 diabetes (T2DM) in Caucasian and non-Caucasian populations. We investigated the contribution of 13 polymorphisms in the promoter, coding regions, and 3′untranslated region of ADIPOQ gene to T2DM in 917 patients and 748 normoglycemic control subjects. ADIPOQ genotyping was done by allelic discrimination method. Of the 13 ADIPOQ variants analyzed, higher minor allele frequency of rs16861194 (P <0.001), rs17300539 (P <0.001), rs266729 (P <0.001), rs822396 (P =0.02), rs2241767 (P =0.03), and rs1063538 (P =0.02) were seen in T2DM cases. Varied association of ADIPOQ genotypes with T2DM was seen according to the genetic model used: rs17300539 and rs266729 were significantly associated with T2DM under the three models, while rs16861194 was association with T2DM under additive and dominant models, and rs822396, rs2241766, and rs1063538 were associated with T2DM under the dominant models only. Haploview analysis revealed low linkage disequilibrium between the ADIPOQ variants, resulting in high haplotype diversity, and two blocks were identified, each differentially associated with T2DM. These results support a significant association of ADIPOQ gene polymorphism with T2DM in Tunisian Arabs. [Copyright &y& Elsevier]

Abstract: IL-18 is a pro-inflammatory cytokine that regulates the differentiation and effector functions of CD4+ (Th1) and CD8+ (CTL) T cells, which are implicated in the pathogenesis of recurrent pregnancy loss (RPL). We investigated the association of the IL-18 gene promoter single nucleotide polymorphisms (SNPs) −656C/A (rs1946519), −137G/C (rs187238), −119A/C (rs360718), and −105G/A (rs360717), by TaqMan assays in analysis in 470 Tunisian women comprising 235 RPL cases and 235 multi-parous controls. The association of IL-18 alleles, genotypes, and haplotypes with RPL was evaluated by Fisher''s exact test and regression analysis. The frequency of minor alleles −105G/A (P <0.001) and −656C/A (P <0.001), but not −119A/C (P =0.93) or −137G/C (P =0.32), were higher in RPL cases. Significant differences were also noted in the genotype distribution of −105G/A (P <0.001) and −656C/A (P <0.001) between cases and controls. Four-locus (−656C/A, −137G/C, −119A/C, −105G/A) IL-18 haplotype analysis identified AGAA (corrected P <0.001), and CGAA (corrected P <0.001) haplotypes to be associated with increased RPL risk, after adjusting for age and BMI. These results demonstrate that −105G/A and −656C/A IL-18 variants are significantly associated with RPL. [Copyright &y& Elsevier]

Abstract: Background: To investigate possible associations of P-selectin polymorphisms with idiopathic recurrent pregnancy loss (RPL). Methods: Study subjects comprised 270 consecutive RPL cases attending outpatient maternity services, and 322 multi-parous control women. P-selectin genotyping was done by PCR-RFLP and PCR-ASA methods. Results: The P-selectin variants rs1800807, rs1800805, and rs6127, were in Hardy Weinberg equilibrium, and low linkage disequilibrium was noted between the three studied SNPs. The frequency of rs6127 A allele (P <0.001I), but not rs1800807 C allele (P =0.957) or rs1800805 A allele (P =0.760), was higher in RPL cases than in control women. Significant differences in the distribution of rs6127 (P <0.001), but not rs1800807 (P =0.444) or rs1800805 (P =0.391) genotypes were seen between cases and controls, and only rs6127 showed a significant association with RPL, with increments of 2.65 and 4.96 in disease risk seen for heterozygous and homozygous carriers, respectively. Among the 8 three-locus Pselectin haplotypes constructed (rs1800807/rs1800805/rs6127), increased frequency of GGG (Pc =0.0249), CGG (Pc =0.0256), and CAG (Pc =0.0174) haplotypes, and lower frequency of CGA haplotype (Pc =0.0091) were seen in RPL cases, thus conferring disease susceptibility and protective nature to these haplotypes, respectively. Conclusions: P-selectin gene polymorphisms and haplotypes contribute to RPL development. [Copyright &y& Elsevier]

Abstract: We investigate in this work the chemical composition by GC–EIMS, the antibacterial and the cytotoxic activities of Tunisian Nigella sativa essential oil and its bioactive compound, thymoquinone, were tested against various clinical cariogenic bacteria (n =30). Eighty-four compounds were identified in the essential oil. The major one was p-cymene (49.48%) whereas thymoquinone represented only 0.79%. The essential oil (2.43mg/disc) containing only 3.35μg of thymoquinone showed pronounced dose dependant antibacterial activity against Streptococcus mitis, Streptococcus mutans, Streptococcus constellatus and Gemella haemolysans (15.5±0.707mm). However, pure thymoquinone compound (150μg/disk) was active against all the studied strains especially S. mutans and S. mitis (24.5±0.71 and 22±1.41mm inhibition zones, respectively). Their MIC values are representatives of a good effect. So, the essential oil strongest activity was seen against S. mitis, S. mutans, S. constellatus and G. haemolysans (MIC 2.13mg/ml). However, thymoquinone was active against all the studied strains. The most important antibacterial activity was seen against S. constellatus (MIC 4μg/ml). The growth inhibition effects of thymoquinone on human epithelial cell lines (Hep-2) were significantly stronger than the essential oil. The IC50 of thymoquinone and essential oil were 19.25±1.6 and 55.2±2.1μg/ml, respectively. Our results demonstrate an important anticariogenic activity of the Tunisian N. sativa essential oil and thymoquinone. These effects further validate the traditional use of N. sativa in the folk medicine against various bacterial infections. [Copyright &y& Elsevier]

Abstract: Objective: Our aim was to evaluate the contribution of tumor necrosis factor (TNF)-α −308G>A and interleukin (IL)-6 −174G>C gene promoter variants to the presence of coronary artery disease (CAD) in Tunisians. Design and methods: Study subjects comprised 418 angiographically proven CAD patients and 406 age-, gender-, and ethnic origin-matched controls. Genotyping was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Results: There were no significant differences in the allelic distribution of TNF-α −308A (19.6% vs. 19.0%, P =0.73), and IL-6 −174C (15.6% vs. 14.3%, P =0.47) promoter polymorphisms between CAD patients and control subjects, respectively. In addition, single locus analysis revealed no differences in genotype frequencies between the two study groups, and the combined distribution of both genotypes did not differ significantly between controls and CAD patients (P >0.05). Conclusion: There is no allelic or genotypic association of TNF-α −308G>A and IL-6 −174G>C promoter polymorphisms with CAD in Tunisians, thereby confirming an ethnic-selective contribution of both gene variants to CAD presence. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Insofar as platelet membrane glycoprotein (GP) polymorphisms were identified as potential risk factors for coronary artery disease (CAD), we investigated the contribution of human platelet antigen (HPA)-1 (GPIIb/IIIa) and HPA-2 (GPIb/IX) alleles and haplotypes to CAD pathogenesis. Methods: Study subjects comprised 247 middle-age CAD patients and 316 age-, gender-, and race-matched controls; HPA genotyping was performed by polymerase chain reaction with sequence specific primers. Results: The frequencies of HPA-1b (P<.001) and HPA-2b (P<.001) alleles and HPA-1a/1b (P<.001), HPA-1b/1b (P<.001), and HPA-2a/2b (P<.001) genotypes were higher in patients than control subjects. Select HPA haplotypes comprising the HPA-1b/2a (Pc=2.2×10−4) and HPA-1b/2b (Pc=.001) haplotypes which were positively associated, and the HPA-1a/2a (Pc=3.2×10−5) which was negatively associated with CAD, confer a disease susceptibility and protective nature to these haplotypes. Multivariate analysis confirmed the positive association of HPA-1b/2a [adjusted odds ratio (aOR)=3.63; 95% CI=2.42–5.43] and HPA-1b/2b (aOR=2.92; 95% CI=1.43–5.94) haplotypes with CAD, after adjustment for a number of covariates. Conclusions: Our results suggest that HPA-1/HPA-2 haplotypes may be considered to be a major risk factor for CAD in middle-aged Tunisians. [Copyright &y& Elsevier]

Aims: Few studies investigated the association of genetic difference in metalloproteinase-2 (MMP-2) gene with diabetic retinopathy but with mixed outcome. To investigate the association between a set of MMP-2 genetic variants and the risk of diabetic retinopathy in an Arab Tunisian population with type 2 diabetes.Subjects and Methods: A retrospective case-control study comprising a total of 779 type 2 diabetes patients with or without diabetic retinopathy was conducted. Genotyping was prepared by TaqMan® SNP genotyping qRT-PCR. The variants used were rs243865 (C/T), rs243864 (T/G), rs243866 (G/T) and rs2285053 (C/T).Results: The minor allele frequency (MAF) of the rs243864 MMP-2 variant was significantly higher among diabetic retinopathy patients. Setting homozygous wild type genotype carrier as reference, the rs243864T/G allele was associated with increased risk of diabetic retinopathy under the dominant, recessive, and additive models which persisted when key covariates were controlled for, while a reduced risk of diabetic retinopathy progression was seen after adjustment between non-proliferative and proliferative diabetic patients. Furthermore, the heterozygous genotype GT of the rs243866 variant is positively associated with the risk of proliferative diabetic retinopathy in the additive model. A limited linkage disequilibrium (LD) was revealed between the four-matrix metalloproteinase-2 variants. Four-loci haplotype analysis identified, GCTC, TTTC, and GCTT haplotypes to be positively associated with the risk of diabetic retinopathy.Conclusion: Our findings demonstrate that the MMP-2 variant rs243864 and 243866 are related to the susceptibility to diabetic retinopathy and the progression of the disease in an Arab Tunisian population with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To investigate the contribution of the −238G/A and −308G/A tumor necrosis factor (TNF) α, and +252A/G lymphotoxin (LT) α gene polymorphisms to idiopathic recurrent miscarriage (RM). Design: A retrospective case-control study. Setting: Outpatient maternity center. Patient(s): Study subjects comprised 372 RM women and 274 age-matched parous control women. Intervention(s): None. Main Outcome Measure(s): The TNFα and LTα gene variants and idiopathic RM. Result(s): Higher prevalence of TNFα −238A and LTα +252G alleles and LTα +252G/G genotype and lower frequencies of TNFα −308G/A were seen in RM cases. Three-loci haplotype analysis (TNFα −308GA/TNFα −238GA/LTα +252AG) demonstrated significant association between TNFα-LTα gene variants and RM. Both protective [−308A/−238G/+252A], and susceptible [−308G/−238A/+252G] haplotypes were identified. Mutlivariate regression analysis confirmed the association of −308G/−238A/+252G haplotype with exclusively early RM, after controlling for a number of covariates; no specific TNFα and LTα genotypes or haplotypes were linked with either late or combined early and late RM. Conclusion(s): The TNFα −238G/A and LTα +252A/G, but not TNFα −308G/A, polymorphic variants are associated with exclusively early idiopathic RM. [Copyright &y& Elsevier]

Abstract: Background: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) mediates a wide range of processes, and abnormal NO production mediated diabetes complications, including diabetic nephropathy (DN). In view of their impact on eNOS activity, polymorphisms in eNOS gene were described as candidates for atherosclerosis and DN. Aims: We evaluated the association of −786T>C (promoter region), Glu298Asp (Exon 7), and 4b4a (Intron 4) polymorphisms in eNOS gene with Type 2 diabetes mellitus (T2DM) and DN by haplotype analysis. Subjects and Methods: Study subjects comprised 515 DN patients, 402 normoalbuminuric [diabetes with no nephropathy (DWN)] T2DM patients, and 748 healthy subjects. −786T>C and Glu298Asp genotyping were done by PCR-RFLP analysis. Results: Higher prevalence of mutant Asp298, 4a, and −786C alleles and homozygous Asp298/Asp298 and 4a/4a genotypes were seen in T2DM patients compared to healthy subjects, with increased Asp298/Asp298 seen in DN compared to DWN patients (P<.05). Three-loci haplotype analysis demonstrated significant association between eNOS variants and T2DM, with protective, neutral, T2DM, and DN-susceptible haplotypes identified, the latter including Asp298/4b/−786T and the Asp298/4a/−786C haplotypes that were present at higher frequencies among DN than among DWN patients. Multivariate regression analysis identified only Asp298/4a/−786T haplotype to be associated with DN (P=.047) after controlling for potential covariates. Conclusion: Genetic variation at the eNOS locus is associated with T2DM. It can serve as a useful genetic marker of increased susceptibility to T2DM and its complications, including the risk of nephropathy. [Copyright &y& Elsevier]

Abstract: Point mutations in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were implicated in the pathogenesis of diabetic nephropathy (DN) in many ethnic groups. This study addressed the association of C677T and A1298C single nucleotide polymorphisms (SNPs) of MTHFR gene with DN in Tunisian type 2 diabetes (T2DM) patients. Study subjects comprised 93 DN patients, 267 patients with normoalbuminuria, and 400 control subjects. C677 T and A1298 C genotypes were determined by PCR-RFLP analysis, and homocysteine levels were measured by ELISA. A1298 C and C677 T were highly prevalent among T2DM patients, with allele frequencies of 0.26 and 0.36, respectively. Higher mutant 677 T allele and 677C/ T and 677 T / T genotypes of C677 T SNP, but not A1298 C SNP, together with 677C/1298A, 677C/1298 C , and 677 T /1298A haplotypes were seen in DN patients compared to normoalbuminuric patients, (p <0.001). Plasma homocysteine was positively associated with MTHFR 677 T / T genotype among the three groups, and was significantly elevated in double heterozygous DN patients but not in normoalbuminuric patients or controls. Logistic regression analysis with DN as dependent variable showed that homocysteine (OR, 1.153) and MTHFR 677 T / T (OR, 9.799) were the only variables associated with DN, after adjusting for possible confounding variables. C677 T , but not A1298 C , SNP, is a risk factor for DN, presumably acting by elevating homocysteine levels. [Copyright &y& Elsevier]

Abstract: Objective: : We assessed the prevalence of inherited (FV-Leiden and PRT G20210A), and acquired (anti-PL antibodies) risk factors among habitual aborters in Tunisia. Study design: : We studied prospectively 146 patients with ≥3 consecutive early, late, or early–late recurrent pregnancy losses, together with 99 age-matched controls. Anticardiolipin antibodies (ACL), lupus anticoagulant (LA), and APC resistance (APCR) were detected by ELISA, dilute Russell Viper Venom Time (dRVVT), and coagulation tests, respectively, and FV-Leiden and PRT G20210A genotypes were assessed by PCR. Results: : Anti-PL antibody frequencies were 45 and 9% among patients and controls, respectively (P < 0.001), with positive LA only (P = 0.004), or combined elevated ACL-positive LA being consistently higher (P < 0.001) among patients than controls. FV-Leiden (20.54% versus 6.06%), but not PRT G20210A (2.74% versus 4.04%) was significantly higher in patients versus controls. Among LA-positive cases higher prevalence of G/A (14/146 versus 1/99) and A/A genotypes (4/146 versus 0/99) were seen, and among ACL-positive cases higher prevalence of G/A (10/146 versus 0/99) and A/A genotypes (2/146 versus 0/99) were recorded. Conclusions: : Anti-PL antibodies and FV-Leiden, but not PRT G20210A, are associated with recurrent idiopathic pregnancy losses in Tunisian women. [Copyright &y& Elsevier]

Aims: Genetic variations mediating MMP-2 expression may result in individual differences in susceptibility to particular diseases. Our aim was to investigate the possible association of certain MMP-2 gene variants with the susceptibility of type 2 diabetes (T2D) in a Tunisian population.Subjects and Methods: A retrospective case-control study involving 310 normoglycemic control subjects and 791 T2D patients was conducted. Genotyping of MMP-2 variants was performed by real time PCR.Results: Minor allele frequencies (MAF) of the rs243865 and the rs243866 MMP-2, were significantly different between T2D cases and controls. Setting homozygous wild-type genotype carrier as reference, a reduced risk of T2D was seen with the rs243865 and the rs243866 genotypes. Haploview analysis revealed limited linkage disequilibrium between the tested MMP-2 and variants, with most haplotypes (99.5%) captured by 7 MMP-2 haplotypes. Taking the GCCC haplotype as reference for MMP-2 (OR = 1.00), a reduced frequency of TTCC haplotypes (P = 0.04) and the GTCC haplotype (P = 3.5 · 10-5) was noted in T2D which indicates a protective nature of these two haplotypes for T2D development.Conclusion: To the best of our knowledge, the present study is the first to demonstrate a consistent association of the rs243865 and rs243866 genotype with a protection for T2D. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the impact of gender on T2DM association with confirmed susceptibility loci. CDKN2A/2B rs10811661, KCNJ11 rs5219, and TCF7L2 rs7903146 were associated with T2DM in females, while POLI rs488846 was associated with T2DM among males; the association of SLC30A8 rs13266634 and TCF7L2 rs4506565, rs12243326, and rs12255372 with T2DM was gender-independent. [Copyright &y& Elsevier]