Khaled Lasram

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

Phylogeny and genetic structure of Tunisians and their position within Mediterranean populations

Abstract Tunisia is located at the crossroads of Europe, the Middle East and Sub-Saharan Africa. This position might lead to numerous waves of migrations, contributing to the current genetic landscape of Tunisians. In this study, we analyzed 815 mitochondrial DNA (mtDNA) sequences from Tunisia in order to characterize the mitochondrial DNA genetic structure of this region, to construct the processes for its composition and to compare it to other Mediterranean populations. To that end, additional 4206 mtDNA sequences were compiled from previous studies performed in African (1237), Near Eastern (231) and European (2738) populations. Both phylogenetic and statistical analyses were performed. This study confirmed the mosaic genetic structure of the Tunisian population with the predominance of the Eurasian lineages, followed by the Sub-Saharan and North African lineages. Among Tunisians, the highest haplogroup and haplotype diversity were observed in particular in the Capital Tunis. No significant differentiation was observed between both geographical (Northern versus Southern Tunisia) and different ethnic groups in Tunisia. Our results highlight the presence of outliers and most frequent unique sequences in Tunisia (10.2%) compared to 45 Mediterranean populations. Phylogenetic analysis showed that the majority of Tunisian localities were closer to North Africans and Near Eastern populations than to Europeans. The exception was found for Berbers from Jerba which are clustered with Sardinians and Valencians.

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.

E23K variant in KCNJ11 gene is associated with susceptibility to type 2 diabetes in the Mauritanian population

AIMS Many genetic association studies reported the contribution of KCNJ11 gene to type 2 diabetes susceptibility in different populations. We aimed to evaluate the association between E23K variant of KCNJ11 and type 2 diabetes in the Mauritanian population. MATERIALS AND METHODS We performed a case-control association study including 135 type 2 diabetes Mauritanian patients and 135 controls. Genotyping for the E23K variant was performed using a TaqMan allelic discrimination assay. RESULTS We found significant association between KCNJ11 E23K variant and type 2 diabetes (Global model, OR=2.08, 95% CI=1.09-3.97, p=0.026). In the Moor ethnic group, E23K was also associated with type 2 diabetes in the general model (OR=2.08, 95% CI=1.09-3.97, p=0.026) and under the dominant model (OR=2.49, 95% CI=1.12-5.55, p=0.026). In the Mauritanians of African descent, KK genotype was not found. Besides, E23K variant was not associated with type 2 diabetes (OR=0.69, 95% CI=0.04-11.32, p=0.793). CONCLUSIONS Our results revealed the risk of type 2 diabetes conferred by KCNJ11 E23K gene variant in the Mauritanian population.

Type 2 diabetes in Mauritania: Prevalence of the undiagnosed diabetes, influence of family history and maternal effect

AIM We estimated the prevalence of undiagnosed diabetes, analyzed the influence of family history on the occurrence of T2D and evaluated its aggregation pattern in the Mauritanian population. METHODS The prevalence of unknown diabetes was obtained using data compiled from 1278 Mauritanian adults applying a questionnaire and fasting serum glucose tests. Detailed family history of diabetes and clinical characteristics were gathered from 421 T2D patients. RESULTS The prevalence of undiagnosed diabetes was 4.7 ± 1.2% in the studied population (3.1% in men and 6.4% in women). 27% of T2D patients reported at least one relative with diabetes. Association between family history and diabetes was higher among first degree compared to second degree relatives (p=0.003). We observed more probands with an affected mother than those who have a father with diabetes (p = 0.002), suggesting a preferential maternal effect which did not extend to second degree relatives. CONCLUSIONS These results show that the prevalence of diabetes in the Mauritanian population could be higher than currently thought. Family history screening may be used in the management of this condition in Mauritania.

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.

Estimation of Recent and Ancient Inbreeding in a Small Endogamous Tunisian Community Through Genomic Runs of Homozygosity.

Runs of homozygosity (ROHs) are extended genomic regions of homozygous genotypes that record populations’ mating patterns in the past. We performed microarray genotyping on 15 individuals from a small isolated Tunisian community. We estimated the individual and population genome‐wide level of homozygosity from data on ROH above 0.5 Mb in length. We found a high average number of ROH per individual (48.2). The smallest ROH category (0.5–1.49 Mb) represents 0.93% of the whole genome, while medium‐size (1.5‐4.99 Mb) and long‐size ROH (≥5 Mb) cover 1.18% and 0.95%, respectively. We found that genealogical individual inbreeding coefficients (Fped) based on three‐ to four‐generation pedigrees are not reliable indicators of the current proportion of genome‐wide homozygosity inferred from ROH (FROH) either for 0.5 or 1.5 Mb ROH length thresholds, while identity‐by‐descent sharing is a function of shared coancestry. This study emphasizes the effect of reproductive isolation and a prolonged practice of consanguinity that limits the genetic heterogeneity. It also provides evidence of both recent and ancient parental relatedness contribution to the current level of genome‐wide homozygosity in the studied population. These findings may be useful for evaluation of long‐term effects of inbreeding on human health and for future applications of ROHs in identifying recessive susceptibility genes.

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.

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

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.

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.