Differential impact of consanguineous marriages on autosomal recessive diseases in Tunisia.

OBJECTIVES: Consanguinity is common in Tunisia. However, little information exists on its impact on recessive disorders. In this study, we evaluate the impact of consanguineous marriages on the occurrence of some specific autosomal recessive disorders and consider how other factors, such as population substructure and mutation frequency, may be of equal importance in disease prevalence. METHODS: Consanguinity profiles were retrospectively studied among 425 Tunisian patients suffering from autosomal recessive xeroderma pigmentosum, dystrophic epidermolysis bullosa, nonsyndromic retinitis pigmentosa, Gaucher disease, Fanconi anemia, glycogenosis type I, and ichthyosis, and compared to those of a healthy control sample. RESULTS: Consanguinity was observed in 341 cases (64.94%). Consanguinity rates per disease were 75.63, 63.64, 60.64, 61.29, 57.89, 73.33, and 51.28%, respectively. First-cousin marriages were the most common form of consanguinity (48.94%) with the percentages of 55.46, 45.46, 47.87, 48.39, 45.61, 56.66, and 35.90%, respectively. A very high level of geographic endogamy was also observed (93.92%), with the values by disease ranging between 75.86 and 96.64%. We observed an overall excess risk associated to consanguinity of nearly sevenfold which was proportional to the number of affected siblings and the frequency of disease allele in the family. Consanguinity was significantly associated with the first five cited diseases (odds ratio = 24.41, 15.17, 7.5, 5.53, and 5.07, respectively). However, no meaningful effects were reported among the remaining diseases. CONCLUSIONS: This study reveals a variation in the excess risk linked to consanguinity according to the type of disorder, suggesting the potential of cryptic population substructure to contribute to disease incidence in populations with complex social structure like Tunisia. It also emphasizes the role of other health and demographic aspects such as mutation frequency and reproductive replacement in diseases etiology.

Gilbert syndrome acts as a risk factor of developing gallstone among ß hemoglobinopathy Tunisian patients.

BACKGROUND: As a result of chronic hemolysis, hyperbilirubinemia is often observed, leading to the formation of pigment cholelithiasis which could be busted by the presence of uridine diphosphoglucuronosyltransferase 1A1 defects. AIM: Herein, we investigated the effect of glibert mutation on the occurrence of pigment cholelithiasis in Tunisian patients with beta (ß) hemoglobinopathy including sickle cell anemia and ß thalassemia (minor). SUBJECTS AND METHODS: Our study included 151 subjects divided in 75 SCA patients and 76 ß thalassemia patients. Both groups of patients were divided into two sub-groups according to the presence or absence of cholelithiasis. The relationship between A(TA)nTAA variation of UGT1A1 gene, the serum bilirubin level and the occurrence of cholilithiasis was investigated. RESULTS: Our results show a significant association between genotypes carrying variant (TA)7 and hyperbilirubinemia (p<0.05). Furthermore, we demonstrated a significant association between (TA)6/(TA)7 and (TA)7/(TA)7 genotypes with cholelithiasis among sickle cell anemia and thalassemia patients (p<0.05). CONCLUSION: Altogether, our data provide evidence that genotypes (TA)6/(TA)7 and (TA)7/(TA)7 and (TA)7 variant present a risk factor of developing gallstone among ß hemoglobinopathy Tunisian patients.

Prognostic value of Pheochromocytoma of the Adrenal Gland Scaled Score (Pass score) tests to separate benign from malignant neoplasms.

BACKGROUND: Differentiating malignant from benign pheochromocytoma has been challenging when based on histologic features. This is due to the definition of malignant pheochromocytoma which are defined by the presence of metastases. A PASS score was developed and according to many authors, a PASS score> =4 identified potentially malignant tumors. AIM: To assess the prognostic value of PASS score in differentiating benign pheochromocytomas from malignant ones. METHODS: The records of 11 patients with tumors diagnosed as "pheochromocytoma" were identified from 1970 to 2010 in the files of the pathology, intern medicine and biochemistry departments of the Charles Nicolle hospital and Pasteur Institute. Receiver operating characteristics (ROC) curve analysis was performed to evaluate the diagnostic performance of PASS. The logistic model was developed using the 11 predictive variables. Its performance was evaluated by calculating the area under the ROC curve and comparing it with that of the PASS. RESULTS: In benign tumors, The PASS score was <4 in 3 cases and >=4 in 6 cases. In malignant tumors, the PASS score was >=4 in both cases. According to the ROC curve analysis, a PASS equal or superior to 4 identifies malignant pheochromocytoma with a sensitivity of 50% and a specificity of 45%. CONCLUSION: I think that PASS score, despite its low sensitivity, may help to reserve the more aggressive treatment and narrow follow up for potentially malignant tumors. Widespread of this called score with complete clinical data will help to validate these findings and to add other prognostic factors of value that could be a part of this scaled score such as immunohistochemical findings.

[Soluble tranferrin receptor in the biological diagnosis of iron deficiency. Report of 24 cases]. / Apport du récepteur soluble de la transferrine dans le diagnostic biologique de la carence en fer chez l'homme. A propos de 24 cas.

BACKGROUND: In inflammatory diseases, classical parameters of iron status (serum iron, serum ferritin, total iron-binding capacity of transferrin and transferrin saturation) are not very reliable. AIM: The purpose of this study is to investigate soluble transferrin receptor, its index and classical parameters of iron status [serum iron, serum ferritin, total iron-binding capacity of transferrin and transferrin saturation] during iron-deficiency anemia and combined iron deficiency and inflammatory anemia. METHODS: Our study concerned 24 patients: 18 patients with iron-deficiency anemia and 6 patients with combined iron-deficiency and inflammatory anemia. 55 healthy subjects were included as controls. Both groups underwent classical parameters of iron status [serum iron, serum ferritin, total iron-binding capacity of transferrin and transferrin saturation] and measurement of soluble transferrin receptor with its index. RESULTS: In iron-deficiency anemia, total iron-binding capacity of transferrin, soluble transferrin receptor and its index were enhanced, whereas serum iron, ferritinemia and transferrin saturation were low compared to controls. Compared to patients with iron-deficiency anemia, those with combined iron-deficiency and inflammatory anemia showed higher levels of serum iron and ferritinemia. In contrast, soluble transferrin receptor and its index did not vary significantly between both groups. CONCLUSION: Our findings show the interest of soluble transferrin receptor and its index in the detection of iron deficiency during anemia of inflammatory states.

Lack of association between the angiotensin-converting enzyme gene (I/D) polymorphism and diabetic nephropathy in Tunisian type 2 diabetic patients.

OBJECTIVE: The aim of the present study was to investigate whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is associated with diabetic nephropathy and type 2 diabetes in the Tunisian population. DESIGN: A case-control study was conducted among 141 unrelated type 2 diabetic patients with (90 patients) or without nephropathy (51 patients) and 103 non-diabetic controls with normal fasting blood glucose. Genotyping was performed using a nested polymerase chain reaction amplification in order to identify correctly heterozygous individuals. RESULTS: The distribution of DD, ID and II genotypes did not significantly differ between type 2 diabetic patients with or without nephropathy (DD: 44%; ID: 46%; II: 10% vs. DD: 41%; ID: 47 %; II: 12%, respectively). There was also no significant statistical difference between the genotype distribution and allele frequencies of the (I/D) polymorphism in all type 2 diabetic subjects compared to non-diabetic controls with normal fasting blood glucose (DD: 43%; ID: 46%; II: 11% vs. DD: 37%; ID: 48%; II: 15%, respectively). CONCLUSIONS: In the present preliminary study, the (I/D) polymorphism within the ACE gene is likely not associated with diabetic nephropathy nor with type 2 diabetes in the Tunisian studied population.

Familial aggregation and excess maternal transmission of type 2 diabetes in Tunisia.

AIM: To evaluate the degree of familial aggregation of type 2 diabetes mellitus in Tunisia and to investigate transmission patterns of the disease and their relationships with patients' clinical profiles. METHODS: Family history of diabetes and clinical data were collected for 132 unrelated type 2 diabetic Tunisian patients. Diabetes status was recorded for first degree relatives (parents, siblings) and second degree relatives (aunts and uncles from both maternal and paternal sides). Information about family history of diabetes was gathered for a total of 1767 individuals. RESULTS: Familial aggregation of type 2 diabetes was prominent and more important among first degree relatives than among second degree relatives (p = 0.01). Among studied subjects, 70% reported at least one relative with diabetes and 34% had at least one parent with diabetes. Diabetes was more frequent among mothers than fathers of probands (p = 0.03). This maternal effect extends to second degree relatives as diabetes was more common among maternal than paternal aunts and uncles (p = 0.01). There is no significant difference in clinical and metabolic profiles between patients according to transmission patterns of the disease. CONCLUSION: These results suggest familial aggregation and excess maternal transmission of type 2 diabetes in the Tunisian studied population.

Study of the T16189C variant and mitochondrial lineages in Tunisian and overall Mediterranean region.

The mitochondrial DNA (mtDNA) variant T16189C has been investigated in several metabolic diseases. In this study, we aimed to estimate the frequency of the T16189C variant in Tunisian and other Mediterranean populations and to evaluate the impact of this variant on the phylogeny of Mediterranean populations. Blood sample of 240 unrelated Tunisian subjects were recruited from several Tunisian localities. The hypervariable region 1 of the mtDNA were amplified and sequenced. Additional sequences (N = 4921) from Mediterranean populations were compiled from previous studies. The average frequency of T16189C variant in Tunisia (29%) is similar to that observed in North African and Near Eastern populations. Our findings showed positive correlation of the T16189C variant with Sub-Saharan and North African lineages, while a negative correlation was found with the Eurasian haplogroups, reaching its maximum with the Eurasian haplogroup H. The principal component analyses showed a high internal heterogeneity between Tunisian localities. At the Mediterranean scale, Tunisians are closer to North African (Algerian and Moroccan) and Near Eastern populations (Syrians and Palestinians) than to Europeans.

[Variation of biochemical parameters of the first morning urine during month of Ramadan]. / Variations des parametres biochimiques de l'urine du reveil pendant le mois de Ramadan.

The purpose of this study is to evaluate the effect of fluid and diet restriction in fasting on biochemical factors of stone formation. Our study concernes 90 patients divided in three groups: healthy fasting patient (GI), healthy non fasting patient (G2) and non fasting patient with calcium lithiasis (G3). The promotors (oxalate, calcium, uric acid, phosphates) and inhibitors (citrate, magnesium) are statistically significant between G1, G2 and G3, G2. Supersaturation of urine with oxalate, uric acid and brushite are the same for (G1) and (G3) and higher than (G2). Crystalluria is more important in lithiasis subjects compared with healthy non fasting patients (58% vs 11,4%). Oxalate monohydrate (Whewellite) and uric crystal don't exist in the healthy non fasting people but reached 4% and 12% respectively in the lithiasis patient. The crystalluria profil is the same in the heathy fasting patients and calcium lithiasis patients. However healthy patients have equilibria between promotors and inhibitors of crystal formation which minimize the risk of crystalluria and subsequent stone formation.

Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population.

BACKGROUND: The insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) identified through genome-wide association (GWA) studies have been shown to be associated with Type 2 diabetes in various ethnic groups. In this study, we investigated the association of the rs7756992 of CDKAL1 and the rs4402960 of IGF2BP2 with Type 2 diabetes, diabetic complications (nephropathy, retinopathy and cardiovascular disease), obesity and hypertension in a Tunisian population. METHODS: A case-control association study including 200 Type 2 diabetes Tunisian patients (World Health Organization criteria) and 208 controls (age ≥40; fasting plasma glucose <6.1 mmol/L; without first degree family history of diabetes) has been performed. Other parameters such as diabetic nephropathy, diabetic retinopathy, cardiovascular disease, overweight/obesity and hypertension have been also collected. Genotyping was performed using TaqMan technology. RESULTS: A significant association between the rs4402960 and Type 2 diabetes (OR = 1.86, 95% CI = 1.34-2.58, P < 10(-4) ) has been found. Overweight/obese subjects bearing the T-allele have an increased risk to develop Type 2 diabetes (OR = 2.06, 95% CI = 1.40-3.03, P < 10(-4) ). Furthermore, the rs7756992 was found to be associated with the reduced risk of diabetic nephropathy in patients with diabetes (OR = 0.44, 95% CI = 0.27-0.73, P = 0.001). CONCLUSIONS: The present study confirms that the rs4402960 of IGF2BP2 gene is a strong candidate for Type 2 diabetes susceptibility and overweight/obesity risk in the Tunisian population. Interestingly, our data suggest that the rs7756992 of CDKAL1 gene have a protective effect against diabetic nephropathy.

[Prognostic value of high-sensitivity C-reactive protein in assessing intrahospital outcome of unstable angina]. / L'intérêt de la CRP ultrasensible dans l'évaluation du pronostic intrahospitalier de l'angor instable.

Inflammation has been shown to play an important role in the pathogenesis of unstable angina. CRP has been demonstrated to be a reliable marker of prognosis is unstable angina. The aim of this study was to investigate the prognostic value of CRP in assessing short outcome of unstable angina. Our study is a prospective double blinded one. We measured CRP in 33 consecutive patients admitted for unstable angina at the 24th and 48th hour. The mean age is 60 years (30 to 84 years). There were 22 men and 11 women. 8 patients were included in class I of Braunwald classification, 5 were in class II and 20 in class III. 14 patients presented cardiac events. The CRP mean value was significantly higher among these patients (12 mg/l vs 5 mg/l, p < 10.4). Patients having a CRP > or = 3 mg/l have a higher risk of developing complications (66% vs 13%, p = 0.002). Elevation of CRP predicted poor outcome of intrahospital evolution with a sensitivity of 86%, a specificity 68%, a positive and negative predictive values of 66% and 86%. The CRP in our preliminary study is an independent risk factor of early outcome of unstable angina. In association with clinical scores and other cardiac markers will lead to a better identification of high risk patients.

Evidence for association of the E23K variant of KCNJ11 gene with type 2 diabetes in Tunisian population: population-based study and meta-analysis.

AIMS: Genetic association studies have reported the E23K variant of KCNJ11 gene to be associated with Type 2 diabetes. In Arab populations, only four studies have investigated the role of this variant. We aimed to replicate and validate the association between the E23K variant and Type 2 diabetes in Tunisian and Arab populations. METHODS: We have performed a case-control association study including 250 Tunisian patients with Type 2 diabetes and 267 controls. Allelic association has also been evaluated by 2 meta-analyses including all population-based studies among Tunisians and Arabs (2 and 5 populations, resp.). RESULTS: A significant association between the E23K variant and Type 2 diabetes was found (OR = 1.6, 95% CI = 1.14-2.27, and P = 0.007). Furthermore, our meta-analysis has confirmed the significant role of the E23K variant in susceptibility of Type 2 diabetes in Tunisian and Arab populations (OR = 1.29, 95% CI = 1.15-1.46, and P < 10(-3) and OR = 1.33, 95% CI = 1.13-1.56, and P = 0.001, resp.). CONCLUSION: Both case-control and meta-analyses results revealed the significant association between the E23K variant of KCNJ11 and Type 2 diabetes among Tunisians and Arabs.