Abdelmajid Abid

Consanguinity, endogamy, and genetic disorders in Tunisia

Consanguinity refers to marriages between individuals who share at least one common ancestor. In clinical genetics, a consanguineous marriage is defined as a union between two individuals who are related as second cousins or closer, with the inbreeding coefficient (F) equal or higher than 0.0156 (Bittles2001). However, reports on consanguinity rates may sometimes include marriages between third cousins or more distantly related individuals (Hamamy2011). It is estimate that more than 690 million people in the world are consan- guineous (Bittles and Black 2010 ). Middle East, Northern Africa, and South Asia are regions that have historically and culturally had a high rate of consanguineous unions (Al- Awadi et al. 1985; Al-Gazali et al.1997; Jaber et al.1997;Bittles et al.2002; Bener and Alali2006). Recent studieshave shown that 20 % to 50 % of marriages in Arab countries are between relatives (Tadmouri et al. 2009;Bittles2011; Hamamy et al.2011). The rate was 68 % inEgypt (Mokhtar and Abdel-Fattah2001), 51-58 % in Jordan

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.

Contribution of CDKAL1 rs7756992 and IGF2BP2 rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population 在突尼斯人群中，CDKAL1 rs7756992与IGF2BP2 rs4402960的多态性对2型糖尿病、糖尿病并发症、肥胖风险以及高血压的影响

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.

Association study of mitochondrial DNA polymorphisms with type 2 diabetes in Tunisian population

Abstract Mitochondrial DNA (mtDNA) variation may play an important role in the pathogenesis of type 2 diabetes (T2Ds). In this study, we aimed to explore whether mtDNA variants contribute to the susceptibility to T2Ds in a Tunisian population. The hypervariable region 1 (HVS1) of the mtDNA of 64 T2Ds patients and 77 healthy controls was amplified and sequenced. Statistical analysis was performed using the STATA program. Analysis of the total screened variants (N = 88) from the HVS1 region showed no significant difference in the distribution of all polymorphisms between T2Ds and controls, except for the variant G16390A which was more frequent in T2Ds (15.9%) than in controls (5.4%) (p = 0.04). The association of G16390A was not detected after multivariate regression analysis. Similarly, analysis of the distribution of mitochondrial haplogroups within our dataset showed 18 distinct major haplogroups with no significant difference between T2Ds and controls. Except, the weakly association found for the G16390A variant, our results showed that none of the tested polymorphisms from the HVS1 region have a major role in T2Ds pathogenesis in the studied Tunisian population even when taking into account the population stratification.

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.

Association of apolipoprotein A5 gene variants with metabolic syndrome in Tunisian population

AIM OF THE STUDY APOA5 has been linked to metabolic syndrome (MetS) or its traits in several populations. In North Africa, only the Moroccan population was investigated. Our aim is to assess the association between APOA5 gene polymorphisms with the susceptibility to MetS and its components in the Tunisian population. MATERIALS AND METHODS A total of 594 participants from the Tunisian population were genotyped for two polymorphisms rs3135506 and rs651821 located in APOA5 gene using KASPar technology. Statistical analyses were performed using R software. RESULTS The SNP rs651821 increased the risk of MetS under the dominant model (OR=1.91 [1.17-3.12], P=0.008) whereas the variant rs3135506 was not associated with MetS. After stratification of the cohort following the sex, only the variant rs651821 showed a significant association with MetS among the women group. The influence of the geographic origin of the studied population on the genotype distribution of APOA5 variants showed that the variant rs651821 was significantly associated with MetS only for the Northern population. The association analyses of the variants rs651821 and rs3135506 with different quantitative traits of MetS showed a significant association only between the variant rs3135506 and triglycerides levels. CONCLUSION This is the first study reporting the association of APOA5 gene variants with MetS in Tunisia. Our study emphasizes the role of APOA5 variants in the regulation of the triglycerides blood levels. Further studies are needed to confirm the clinical relevance of these associations and to better understand the physiopathology of the MetS.

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

Abstract 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.

Association of genetic variants in the FTO gene with metabolic syndrome: A case-control study in the Tunisian population

AIMS Variants in the fat mass and obesity-associated gene (FTO) are associated with obesity and type 2 diabetes. However, the association of FTO variants in the MENA (Middle East and North Africa) region with MetS is largely unknown. In this study, we aimed to investigate the association of FTO gene with MetS and its components in Tunisian population. METHODS Two variants in the FTO gene were genotyped: rs1421085 T>C and rs8057044 A>G in cases and controls from Tunisian population. Anthropometric and biochemical parameters were assessed. Metabolic syndrome was defined according to the International Diabetes Federation (IDF). RESULTS The FTO rs1421085 variant conferred an increased risk to MetS (OR=1.61, 95% CI=1.14-2.26, P=0.024) that was abolished when adjusted for fasting plasma glucose (FPG), suggesting that the association may be due to variation in FPG levels. Indeed, this variant was associated to FPG (OR = 1.7, 95% CI=1.23-2.44, P=0.002) independently from BMI or age. The second polymorphism rs8057044 was associated with high blood pressure levels (OR=1.45, 95% CI=1.06-1.99, P=0.019). CONCLUSIONS This is the first study highlighting the association between FTO gene variants and MetS in Tunisian population. These findings provide evidence that FTO gene may play a critical role in leading to MetS in Tunisian population.

Pharmacogenetic landscape of Metabolic Syndrome components drug response in Tunisia and comparison with worldwide populations

Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with other neighboring populations, our study has an impact not only on the Tunisian population but also on North African population which are underrepresented in pharmacogenomic studies.

Contribution ofCDKAL1rs7756992 andIGF2BP2rs4402960 polymorphisms in type 2 diabetes, diabetic complications, obesity risk and hypertension in the Tunisian population 在突尼斯人群中，CDKAL1rs7756992与IGF2BP2rs4402960的多态性对2型糖尿病、糖尿病并发症、肥胖风险以及高血压的影响: Polymorphism complications in T2DM Tunisians

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.