Matrix metalloproteinase 3 and 9 as genetic biomarkers for the occurrence of cardiovascular complications in coronary artery disease: a prospective cohort study.

BACKGROUND: Matrix metalloproteinases (MMPs) are widely expressed in atherosclerosis lesions. The disequilibrium of MMPs driving to an overexpression or a lack of its level can be influenced by genetic variations. MMP-3 and MMP-9 may be affected by specific polymorphisms like - 1612 5 A/6A and the - 1562 C/T respectively. We aim in the present study to investigate prospectively the association between the - 1612 5 A/6A MMP-3 and - 1562 C/T MMP-9 polymorphisms and clinical outcomes in patients with coronary artery disease (CAD). This study is elaborated to reveal whether one of these polymorphisms is a probable predictor of cardiovascular complications in this CAD cohort. METHODS AND RESULTS: A total of 168 patients with CAD were prospectively followed up over a period of 5 years. Genotypes for the MMP-3 (-1612 5 A/6A) and MMP-9 (-1562 C/T) polymorphisms were performed using PCR-RFLP. Their levels were measured by ELISA in Sandwich test during the follow-up period, 39 cardiovascular outcomes occurred with 21 repeat targets for revascularization, 3 patients with Myocardial infarction, 8 for heart failure, 5 for Stroke and 2 for cardiovascular mortality. The MMP-3 5 A/6A polymorphism was related to the disease on the contrary of the MMP-9 -1562 C/T. Patients carrying the 5 A allele had a higher level of MMP-3 level and those who carried the 6 A allele had lower level (p = 0.04). After applied multivariable Cox-hazard models we revealed that the 6 A allele is independently associated to the disease complication. Kaplan-Meier survival test revealed that individuals having the 6 A allele had a lower survival rate than those with the 5 A allele (p = 0.04). CONCLUSION: Our study suggests the disruption of the MMP-3 level may be due to the existence of the polymorphism - 1612 residing in its promoter region. MMP-3 can be considered as a marker of diagnosis and prediction in cardiovascular events.

SARS-CoV-2 and pathological matrix remodeling mediators.

BACKGROUND: Recognizing only sharp elevation in a short period of time, the COVID-19 SARS-CoV-2 propagation is more and more marked in the whole world. Induced inflammation afterwards infection engenders a high infiltration of immune cells and cytokines that triggers matrix metalloproteinases (MMPs) activation. These endopeptidases are mediators of the lung extracellular matrix (ECM), a basic element for alveoli structure and gas exchange. METHODS: When immune cells, MMPs, secreted cytokines and several other mediators are gathered a pathological matrix remodeling occurs. This phenomenon tends to tissue destruction in the first place and a pulmonary hypertrophy and fibrosis in the second place. FINDINGS: After pathological matrix remodeling establishment, pathological diseases take place even after infection state. Since post COVID-19 pulmonary fibrosis is an emerging complication of the disease, there is an urge to better understand and characterize the implication of ECM remodeling during SARS-CoV-2 infection. CONCLUSION: Targeting MMPs and their inhibitors could be a probable solution for occurred events since there are many cured patients that remain with severe sequels even after the end of infection.

Circulating MMP-7 and VEGF as potential predictive biomarkers for recurrent implantation failures.

Recurrent implantation failure (RIF) is considered to be one of the major limiting factors of assisted reproductive technology (ART) programme success. The current study focused on the investigation of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), cytokines and cell adhesion molecules in peripheral blood (PB) and follicular fluid (FF) obtained from 44 women aged between 25 and 39 years old and undergoing intracytoplasmic sperm injection (ICSI). These women were divided into two groups: 22 RIF women with embryo implantation failures after the transfer of at least four fresh or frozen-thawed good quality embryos in a minimum of three ICSI cycles, and 22 ICSI success women (controls) who achieved a clinical pregnancy at their first ICSI attempt. The PB and FF samples were obtained from each patient on the day of oocyte retrieval. MMP-1, -2, -3, -7, -9, TIMP-1, -2, vascular endothelial growth factor (VEGF), leukaemia inhibitory factor (LIF), vascular cell adhesion molecule 1 (VCAM1) and intercellular adhesion molecules 1 (ICAM1) were analyzed using enzyme-linked immunosorbent assay of PB and FF. Our results showed significant decreases in PB MMP-7 and PB VEGF in the RIF group compared with controls [281.11 (33-614) pg/ml vs 119.92 (27-441) pg/ml; P-value = 0.030] and [82.54 (25.94-210.20) pg/ml vs 30.93 (13.62-193.33) pg/ml; P-value = 0.022; respectively]. Receiver operating characteristic (ROC) curve analysis showed informative area under the curve values for PB MMP-7, as well as for PB VEGF, making them able to be proposed as biomarkers of the RIF. Therefore, circulating MMP-7 and VEGF seem to play an interesting role in embryo implantation in in vitro fertilization (IVF)/ICSI cycles and could be proposed as circulating biomarkers of the RIF. These results could be helpful for clinicians and patients to choose the best rescue strategy and treatment to minimize implantation failure in women undergoing IVF/ICSI procedures after the first attempt.

Matrix metalloproteinase-7 could be a predictor for acute inflammation in psoriatic patients.

PURPOSE: The pathogenesis of psoriasis is characterized by a disruption of extracellular matrix (ECM) in which matrix metalloproteinases (MMPs) participate actively. We aimed to determine MMP-7 level and its association with the inflammatory response in order to determine its usefulness as a biomarker for psoriasis prediction. We also aimed to determine its distribution in uninvolved and involved psoriatic skin to evaluate the probable role of MMP-7 in psoriasis pathogenesis. MATERIALS AND METHODS: We recruited 108 psoriatic patients and 133 healthy controls. MMP-7, tissue inhibitors of metalloproteinases (TIMPs) and interleukin-6 (IL-6) levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA) assay. MMP-7 expression was detected by Immunohistochemistry (IHC) study. RESULTS: ECM turnover and inflammatory biomarker levels were significantly higher in psoriatic patients. MMP-7 revealed to be independently associated to psoriasis even after adjustment for different models. The area under the curve (AUC) of MMP-7 and inflammation Z-score were similar. MMP-7 was positively correlated with IL-6 and inflammation Z-score. Psoriasis severity (PASI) was correlated significantly with IL-6 (p = 0.007). The MMP-7 expression was detected in the epidermis of involved and uninvolved psoriatic skin. In involved skin, MMP-7 was expressed by basal and mostly suprabasal keratinocytes. In uninvolved skin, expression of MMP-7 was restricted to basal keratinocytes. CONCLUSION: MMP-7 is independently associated to psoriasis disease and to inflammatory response which make it a potential biomarker for this dermatosis.

Matrix metalloproteinase-3 predicts clinical cardiovascular outcomes in patients with coronary artery disease: a 5 years cohort study.

Matrix metalloproteinases (MMPs) are implicated in atherosclerosis evolution into a coronary artery disease (CAD). They could be used as biomarkers for a predictive approach when they are studied simultaneously. We aim in our study to demonstrate prospectively in patients with history of CAD that MMPs level is linked to clinical cardiovascular outcomes. Two hundred and eighteen patients diagnosed with CAD were followed prospectively for 5 years in the Cardiology Department of la Rabta Hospital University. Clinical cardiovascular outcomes during the period of the cohort were recorded. Measures were performed for biological and matrix markers at baseline. MMP-3, MMP-8, MMP-9, TIMP-1 and TIMP-2 were measured by ELISA in Sandwich assay. Fifty-nine cardiovascular outcomes occurred during the cohort period. By multivariate analysis, only MMP-3 persisted as a predictor for cardiovascular events even after adjustment. This metalloproteinase have been shown to be an independent predictor for cardiovascular outcomes (HR = 3.01; CI (1.3-6.95). The found cut-off value by receiver operating curve (ROC) was used for Kaplan-Meier analysis and revealed that patients with MMP-3 level higher than 9.3 ng/mL had a lower survival rate (p = 0.03). MMP-3 baseline level in patients with history of CAD is a potential predictor for cardiovascular outcomes.

Does the dysregulation of matrix metalloproteinases contribute to recurrent implantation failure?

INTRODUCTION: The progress in in vitro fertilization (IVF) techniques for infertility management has led to the investigation of embryo implantation site proteins such as Matrix metalloproteinases (MMPs), which may have a key role in embryo-endometrium crosstalk and in the molecular mechanisms of the embryo implantation. Areas covered: Numerous studies have generated much information concerning the relation between the different proteins at the site of implantation such as cytokines, growth factors, adhesion molecules and MMPs. However, the exact role of the MMPs in embryo implantation and the impact of their dysregulation in recurrent implantation failure have yet to be characterized. Expert commentary: The proteomic investigation of the MMPs and their molecular pathways may enable scientists and clinicians to correct this dysregulation (via appropriate means of prevention and treatment), better manage embryo transfer during IVF cycles, and thus increase the ongoing pregnancy rate.

Association of matrix metalloproteinase 3 and endogenous inhibitors with inflammatory markers in mitral valve disease and calcification.

Calcific mitral valve stenosis (MVS) is a common disease characterized by extensive remodeling of the extracellular matrix via matrix metalloproteinases (MMPs). The mechanism of calcification due to extensive matrix remodeling remains unclear. In this study, we investigated the relationship between MMP-3, tissue inhibitors of metalloproteinases (TIMPs) as well as pro-inflammatory cytokines and the phenomenon of calcification in MVS. 212 patients having rheumatic mitral stenosis (RMS) and 155 healthy control subjects were recruited in the Cardiology Department of La Rabta Hospital University. Levels of MMP-3, TIMPs, IL-6 and TNF-α were measured by ELISA sandwich assay, hs-CRP was measured by immunoturbidimetry. Plasma levels of MMP-3, TIMP-1 and MMP-3/TIMP-2 ratio were lower only in RMS women in comparison to the control group. Calcification degree correlated positively with MMP-3 in women and men. In addition, calcification was correlated positively with MMP-3/TIMPs ratio in women patients. The inflammatory parameters were positively associated with extracellular matrix turnover biomarkers in men patients. In patients, the level of MMP-3 was increased in men and women with a calcification score ≥ 5. In addition, MMP-3 level predicted the occurrence of calcification. At ROC curves analysis, the cut-off MMP-3 level was in women was 9.21 ng/ml (sensitivity 51.1%, specificity 89.3%) and in men was 12.84 ng/ml (sensitivity 78.6%, specificity 77.8%). The high levels of MMP-3 and the biomarkers of inflammation contribute to valvular remodeling and calcification of the mitral valve.

Inflammations mediators and circulating levels of matrix metalloproteinases: Biomarkers of diabetes in Tunisians metabolic syndrome patients.

AIMS: This study investigates the relationships between matrix metalloproteinases, inflammations mediators and type 2 diabetes mellitus in Tunisians metabolic syndrome (Mets) patients. METHODS: The study has included 239 MetS patients and 247 controls. Mets was defined according to the NCEP-ATPIII report. Mets patients were also divided into two categories: 29 MetS non-diabetics and 210 MetS diabetics. Dysglycemia markers, matrix metalloproteinase-9 (MMP-9), Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), tumor necrosis factor α (TNF-α), C-reactive protein (CRP) levels and White Blood Cells (WBC) counts were determined in patients and controls. RESULTS: In our study, the level of inflammatory markers WBC, TNF-α and matrix metalloproteinases (MMP-8 and MMP-9) were significantly higher in diabetic patients with MetS, as compared with non-diabetic MetS patients. Inflammation mediators and MMP-9 were significantly associated with many clinical characteristics of MetS. The use of ROC "Receiver Operating Characteristic" analysis revealed the impact of TNF alpha on diabetes patients with MetS. In fact TNF alpha was found as a sensitive parameter in these patients with a sensitivity of 85%. CONCLUSION: Inflammation, matrix metalloproteinases and dysglycemia markers are not expressed in isolation but rather concurrently and are continuously interacting with each other, in MetS and diabetics patients. These markers fit with an early stage of cardiovascular disease (CVD); and measuring them could improve the risk evaluation, an early diagnosis, and the prognosis of CVD.

Abnormal Circulating Levels of Metalloproteinase and Their Inhibitor in Hypertensive Patients.

BACKGROUND: The aim of this study was to determine the plasmatic levels matrix metalloproteinases (MMPs): MMP-2, MMP-3, MMP-9, and their inhibitors (TIMPs): TIMP-1 and TIMP-2 in hypertensive patients and healthy subjects. METHODS: The study involved 60 hypertensive patients and 61 adult healthy controls. Pro-MMP-9 and pro-MMP-2 activity was determined by the gelatin zymography method and MMP-3, TIMP-1, and TIMP-2 levels were determined by ELISA method. RESULTS: The mean plasma activity of pro-MMP-9 in the hypertensive group and the control group were significantly different (153.33 ± 129.33 vs. 90.38 ± 97.49 x 10(3) densitometric units/µL; p < 0.01). MMP-3 plasmatic level was significantly higher in hypertensive subjects than healthy subjects (20.24 ± 8.63 vs. 16.41 ± 6.8 ng/mL; p < 0.05), whereas the plasma concentration of TIMP-1 in the hypertensive group was lower than the control group 88.96 ± 26.9 vs. 93.96 ± 27.28 ng/mL. The MMP-3/ TIMP-1 and the MMP-3/TMP-2 ratios were higher in hypertensive subjects than healthy subjects. Also, we have found a significant positive correlation between systolic blood pressure and pro-MMP-9 (r = 0.311, p < 0.001). CONCLUSIONS: The present study identified the existence of abnormalities in plasma markers for extracellular matrix metabolism in hypertensive patients.

Metabolic Syndrome, Independent Predictor for Coronary Artery Disease.

BACKGROUND: Metabolic syndrome (MS) was reported to be associated with coronary artery disease (CAD). The aim of the present study was to assess the association between MS and CAD angiographic severity and to search the predictive value of MS and its individual components for CAD. METHODS: 428 patients who underwent elective coronary angiography at the Cardiology Department were included in the study. MS was defined according to National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. CAD severity was determined by Gensini scors. RESULTS: The proportion of CAD (+) who had MS was significantly higher compared to CAD (-) (63.6% vs. 48.6%, p = 0.020). Gensini score and number of MS components were positively correlated (r = 0.144, p = 0.019). The adjusted predictive abilities for angiographic CAD of MS and its individual components showed that high FBG and high TG are predictive factors for CAD in binary logistic regression analysis (OR = 2.238, 95% CI 1.111 - 4.508, p = 0.024 vs. OR = 2.200, 95% CI 1.078 - 4.492, p = 0.030). The OR for CAD risk of different phenotypes in high FBG and/or HTG shows that this combination increased the OR significantly to 2.307. Among the quartets, the cluster with high BP and low HDL-C was the highest risk (OR = 4.879). However, the combination including all components of MS was a significant contributor to CAD risk. CONCLUSIONS: The MS score correlates with the angiographic severity of CAD. The predictive ability for CAD was stronger with high FBG and high TG and associated low HDL-C and high BP, which seem to act synergistically as risk factors for CAD. Therefore, to prevent or decrease this risk of CAD, clinicians should screen for individual abnormalities of MS, mainly elevated blood glucose level and TG.

Plasma total homocysteine: usual values and main determinants in adults living in the Great Tunis region.

BACKGROUND: Elevated total plasma homocysteine (tHcy) is an established risk factor for occlusive vascular disease and is thought to increase the risk of pregnancy loss, birth defects, and cognitive impairment in the elderly. OBJECTIVES: To determine tHcy standard values and the prevalence of hyperhomocysteinemia (HHC) and to examine their association with demographic and life style factors in the Greater Tunis population. METHODS: This cross-sectional study included 2712 subjects (1228 males and 1484 females) aged 35 - 70 years, living in the Greater Tunis region. tHcy was analyzed by a fluorescent polarizing immunoassay method. HHC was considered as tHcy > or = 15 micromol/L. RESULTS: HHC was observed in 23.7% of subjects. Plasma tHcy was higher in males than females (median (5th - 95th percentile): 13.5 [8.75 - 26.3] micromol/L vs. 10.7 [6.94 - 19.6] micromol/L). The tHcy concentration was significantly increased in smokers, alcoholics, in subjects with vitamin B12 and folate deficiencies, and hyperuricemia. In multivariate analysis, HHC was associated with male gender, vitamin B12 deficiency, clearance of creatinine, alcohol consumption, and hyperuricemia. CONCLUSIONS: HHC is common in Tunisian adults. Male gender, advanced age, renal insufficiency, low vitamin B12 status, hyperuricemia, and alcohol consumption are the main determinants of HHC in this population.

The measurement of circulating matrix metalloproteinase-8 and its tissue inhibitor and their association with inflammatory mediators in patients with acute coronary syndrome.

BACKGROUND: The aim of the present study was to investigate differences of matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients admitted with acute coronary syndrome (ACS) and its correlation with the widely accepted markers of inflammatory activity, C-reactive protein, fibrinogen, and white blood cell number. METHODS: 315 patients with ACS (165 unstable angina pectoris/non-ST-elevation myocardial infarction, 150 ST elevation myocardial infarction), 111 stable angina (SA) patients, and 296 control subjects were enrolled in the study. All biochemical analyses were carried out using a Hitachi 912 analyzer (Roche). Matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in citrate plasma by ELISA methods. White blood cells (WBC) and fibrinogen were also determined. RESULTS: The plasma concentrations of matrix metalloproteinase-8, tissue inhibitor of metalloproteinase-1, C-reactive protein, fibrinogen, and WBCs in patients with acute coronary syndrome were significantly higher than those in the control group (p < 0.001). Strong positive associations were observed between MMP-8 and TIMP-1 (r = 0.328, p < 0.001), MMP-8 and CRP (r = 0.171, p < 0.001), MMP-8 and Fibrinogen (r = 0.267, p < 0.001), MMP-8 and WBC (r = 0.163, p < 0.01), TIMP-1 and CRP (r = 0.219, p < 0.01), TIMP-1 and fibrinogen (r = 0.226, p < 0.01), TIMP-1 and WBC (r = 0.094, p < 0.1). Other positive correlations were observed between CRP and fibrinogen, CRP and WBC and fibrinogen and WBC in the patients with ACS. CONCLUSIONS: Observations suggest that ACS show an increase in both remodeling and inflammation markers. In addition, the strong relationship with MMP-8 and inflammatory mediators such as CRP, fibrinogen and WBC in ACS patients suggests that MMP-8 might be an additional marker and/or consequence of inflammatory components in ACS.

Single-center experience of congenital disorders of glycosylation syndrome screening in Tunisia: A retrospective study over a 15-year period (2007-2021).

BACKGROUND: We report the results gathered over 15 years of screening for congenital disorders of glycosylation syndrome (CDGS) in Tunisia according to clinical and biochemical characteristics. METHODS: Our laboratory received 1055 analysis requests from various departments and hospitals, for children with a clinical suspicion of CDGS. The screening was carried out through separation of transferrin isoforms by capillary zone electrophoresis. RESULTS: During the 15-year period, 23 patients were diagnosed with CDGS (19 patients with CDG-Ia, three patients with CDG-IIx, and one patient with CDG-X). These patients included 13 boys and 10 girls aged between 3 months and 13 years, comprising 2.18 % of the total 1055 patients screened. The incidence for CDGS was estimated to be 1:23,720 live births (4.21 per 100,000) in Tunisia. The main clinical symptoms related to clinical disease state in newborn and younger patients were psychomotor retardation (91 %), cerebellar atrophy (91 %), ataxia (61 %), strabismus (48 %), dysmorphic symptoms (52 %), retinitis pigmentosa, cataract (35 %), hypotonia (30 %), and other symptoms. CONCLUSION: In Tunisia, CDGS still remains underdiagnosed or misdiagnosed. The resemblance to other diseases, especially neurological disorders, and physicians' unawareness of the existence of these diseases are the main reasons for the underdiagnosis. In routine diagnostics, the screening for CDGS by biochemical tests is mandatory to complete the clinical diagnosis.

Peripheral blood levels of matrix and inflammatory mediators are elevated in Tunisian patients with acute coronary syndromes.

BACKGROUND: The aim of the present study was to investigate differences of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients admitted with acute coronary syndrome (ACS), in correlation with the widely accepted markers of inflammatory activity, C-reactive protein, fibrinogen, and white blood cell number. METHODS: 315 patients with ACS (165 unstable angina pectoris/non-ST-elevation myocardial infarction, 150 ST-elevation myocardial infarction), 111 stable angina (SA) patients, and 296 control subjects were enrolled in the study. All biochemical analyses were carried out using a Hitachi 912 analyzer (Roche). Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were determined in citrate plasma by ELISA methods. White blood cells (WBC) and fibrinogen were also determined. RESULTS: The plasma concentrations of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, C-reactive protein, fibrinogen, and white blood cells in patients with acute coronary syndrome were significantly elevated compared to the control group (p < 0.001). MMP-9/TIMP-1 ratio was significantly higher in SA and ACS patients (p < 0.001) than controls. Strong positive associations were observed between MMP-9 and TIMP-1 (r = 0.213, p < 0.01), MMP-9 and CRP (r = 0.103, p < 0.01), MMP-9 and fibrinogen (r = 0.299, p < 0.01), MMP-9 and WBC (r = 0.135, p < 0.01), TIMP-1 and CRP (r = 0.219, p < 0.01), TIMP-1 and Fibrinogen (r = 0.226, p < 0.01), TIMP-1 and WBC (r = 0.094, p < 0.1), CRP and fibrinogen (r = 0.158, p < 0.01), CRP and WBC (r = 0.156, p < 0.01, and finally between fibrinogen and WBC (r = 0.234, p < 0.01) in the patients with ACS. CONCLUSIONS: In conclusion, our observations suggest that ACS shows an increase in both remodeling and inflammation markers. In addition, the strong relationship with MMP-9 and inflammatory mediators such as CRP, fibrinogen, and WBC in ACS patients suggests that MMP-9 might be an additional marker and/or consequence of inflammatory components in ACS.

Dyslipidemia in the Greater Tunis population: prevalence and determinants.

BACKGROUND: Economic development and socio-demographic changes have led to increased frequency of cardiovascular disease and other chronic diseases in Tunisia. OBJECTIVES: To assess the prevalence of different types of dyslipidemia and to examine their association with sociodemographic characteristics in the Greater Tunis population. METHODS: The study included 2712 subjects (1228 men and 1484 women) aged 35-70 years, recruited during the years 2004 and 2005 from the Greater Tunis population. Hypercholesterolemia, hypertriglyceridemia, and low HDL cholesterol were defined according to the National Cholesterol Education Program-Adult Treatment Panel III. RESULTS: The prevalence of hypercholesterolemia, hypertriglyceridemia, and low HDL cholesterol was 40.8% (34.9% in males and 45.8% in females; p < 0.001), 29.2% (31.1% in males and 27.6% in females; p < 0.05), and 21.2% (32.5% in males and 11.5% in females; p < 0.001), respectively. The prevalence was higher in urban than rural regions. Hypercholesterolemia was more frequent in illiterate women and in men with high education level. CONCLUSIONS: Dyslipidemias are common in Tunisians, mainly in urban areas, in illiterate women as well as in men with high levels of education. Profound changes of life style and dietary habits of Tunisians are needed to reduce the risk of cardiovascular diseases.

Abnormal circulating levels of matrix metalloproteinases and their inhibitors in diabetes mellitus.

BACKGROUND: The aim of this study was to determine plasma levels of matrix metalloproteinases (MMPs) 2, 3, and 9 and their tissue inhibitors (TIMPs) 1 and 2 in type 2 diabetic patients (T2DM) compared to healthy subjects. METHODS: The study involved 54 patients with T2DM and 57 age and gender matched healthy adults as controls. MMPs 2 and 9 were analyzed by gelatin zymography and MMP-3 and TIMPs 1 and 2 by ELISA. RESULTS: For technical feasibility, MMPs 2 and 9 were expressed in pro forms. Pro-MMP-9 was significantly higher (p < 0.05), whereas TIMP-1 and TIMP-2 levels were significantly decreased (p < 0.01) in patients with T2DM compared to controls. The MMP-3/TIMP-1 and the MMP-3/TMP-2 ratios were significantly higher in T2DM patients than controls (p < 0.05). Fasting plasma glucose was inversely correlated with TIMP-1 (r = -0.412, p < 0.01) and TIMP-2 (r = -0.315, p < 0.001), but was not associated with MMPs. CONCLUSIONS: The present study identified abnormalities in plasma markers for extracellular matrix metabolism in T2DM. The new parameters would constitute an effective approach to explore the complications of uncontrolled diabetes.

Aminoacidopathies and organic acidurias in Tunisia: a retrospective survey over 23 years.

BACKGROUND: Inborn errors of metabolism are neglected in developing countries because they are not as common as infectious and nutritional disorders. In Tunisia, no information is available on the incidence and epidemiological features of these inherited metabolic diseases. AIMS: To precise the profile of aminoacidopathies other than phenylketonuria and organic acidurias and to estimate their incidences in Tunisia. METHODS: Between 1987 and 2009, our laboratory received 13171 requests for analysis of patients with symptoms suggestive of inborn errors of metabolism. For these cases, ion exchange chromatography of free amino acids was performed on amino acids analyser. Urinary organic acids profiles were determined by gas chromatography-mass spectrometry. RESULTS: Abnormal cases were 370 (2.8%), divided into 212 cases of aminoacidopathies (57.3%) and 158 cases of organic acidurias (42.7%). The most frequent aminoacidopathies, were maple syrup disease (32.5%), tyrosinemia type I (28.8%) and nonketotic hyperglycinemia (16%). Methylmalonic aciduria (33.5%), propionic aciduria (18.4%) and 2-hyrdoxy glutaric aciduria (10.8%) were the most frequent organic acidurias. The incidences were calculated using the Hardy-Weinberg formula and were estimated at 1/13716 for maple syrup disease, 1/14804 for tyrosinemia type I, 1/16144 for methylmalonic aciduria and 1/23176 for propionic aciduria. CONCLUSION: Aminoacidopathies and organic acidurias turned out to be highly frequent in Tunisia, mainly because of a high rate of consanguinity. We believe that they are underestimated. To improve their diagnosis, it is necessary to have available sophisticated equipment which would allow early treatment of patients.

Association between -786TC polymorphism in the endothelial nitric oxide synthase gene and hypertension in the Tunisian population.

BACKGROUND: Nitric oxide (NO) is produced by endothelial cells and serves as a potent vasodilator. Several lines of evidence have shown that NO plays an important role in the regulation of blood pressure and regional blood flow. Recent genetic studies have shown an association between the -786TC polymorphism in the endothelial nitric oxide synthase gene (NOS3) and coronary artery diseases, but any possible association with hypertension has been controversial. In the present study, we examined a possible association between the -786TC polymorphism of the NOS3 gene and hypertension in a sample of the Tunisian population. METHODS: A total of 288 unrelated Tunisian patients with hypertension and 373 normotensive subjects were included in the study. The -786TC gene polymorphism was analyzed by PCR-RFLP. RESULTS: A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with hypertension had a frequency of 19.7% for CC genotype, 52.9% for TC genotype and 27.3% for TT genotype. The control had a frequency of 14.7% for the CC genotype, 47.2% for the TC genotype and 38.1% for the TT genotype (χ²=9.09, p=0.01). The hypertension patient group showed a significant higher frequency of the C allele compared to the controls (0.46 vs. 0.38; χ²=8.26, p=0.004). The odds ratio of hypertension for C vs. T allele frequencies was statistically significant 1.59 (1.14-2.21) at 95% CI, p = 0.004 in men, whereas it was non-significant in women 1.21 (0.87-1.67), p=0.23. CONCLUSION: The present study showed a significant and independent association between the -786TC gene polymorphism (presence of C allele) and hypertension in the Tunisian population.

C(-260)T polymorphism in the promoter of CD 14 gene is not associated with myocardial infarction in the Tunisian population.

Recent findings suggest that inflammation plays a role in atherosclerosis and its acute complications. Several known mechanisms may play at least a partial role in this process. One of the most likely mechanisms involves lipopolysaccharide (LPS) and its receptor, CD14. The C(-260)T single nucleotide polymorphism (rs2569190) in the promoter region of the CD14 receptor gene has been reported to be associated with a higher risk of MI. Others studies, however, have not corroborated these findings. Considering the contradictory results, the aim of the present study was to investigate the possible association between the CD14 C(-260)T polymorphism and the risk of MI in the Tunisian population. A total of 321 Tunisian patients with MI and 344 healthy controls were included in the study. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The frequency of TT homozygous genotype for the CD14 C(-260)T polymorphism was 26.2% in MI patients and 27.0% in the control group. However, the genotype distribution and allele frequencies were not significantly different between MI and controls subjects. Moreover, the odds ratio for MI associated with the TT genotype failed to reach statistical significance (OR=1.22; 95% CI: 0.85-1.77; p=0.272). These results do not support the hypothesis that the C-260T polymorphism of CD14 gene contributes to the genetic susceptibility to MI in the Tunisian population studied.

Association between the -2518G/A polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene and myocardial infarction in Tunisian patients.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1; gene name CCL2) has been suggested to play an important role in the initiation of atherosclerosis by recruiting monocytes to sites of injured endothelium. Recently, single nucleotide polymorphisms (SNPs) in the MCP-1 regulatory region have been identified. Controversial results regarding the association of the -2518G/A polymorphism of the MCP-1 gene with coronary artery disease (CAD) have been reported. In the present study, we examined a possible association between the -2518G/A polymorphism of the MCP-1 gene and myocardial infarction (MI) in a sample of the Tunisian population. METHODS: A total of 319 Tunisian patients with MI and 467 healthy controls were included in the study. The SNP of the MCP-1 gene was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Patients with MI had significantly higher frequency of the AG+GG genotypes compared to controls [42.9% vs. 35.8%; OR (95%CI), 1.34 (1.00-1.79); p=0.04]. The MI patient group showed a significant higher frequency of the G allele compared to the controls [0.242 vs. 0.195; OR (95%CI), 1.31(1.02-1.68), p=0.03]. The association between the -2518G/A polymorphism of the MCP-1 gene and MI was no longer significant after adjustment for other well-established risk factors. CONCLUSION: The present study showed a significant but not independent association between the -2518G/A polymorphism of the MCP-1 gene (presence of G allele) and MI in the Tunisian population.