Genetic diversity of variants involved in drug response among Tunisian and Italian populations toward personalized medicine.

Adverse drug reactions (ADR) represent a significant contributor to morbidity and mortality, imposing a substantial financial burden. Genetic ancestry plays a crucial role in drug response. The aim of this study is to characterize the genetic variability of selected pharmacogenes involved with ADR in Tunisians and Italians, with a comparative analysis against global populations. A cohort of 135 healthy Tunisians and 737 Italians were genotyped using a SNP array. Variants located in 25 Very Important Pharmacogenes implicated in ADR were extracted from the genotyping data. Distribution analysis of common variants in Tunisian and Italian populations in comparison to 24 publicly available worldwide populations was performed using PLINK and R software. Results from Principle Component and ADMIXTURE analyses showed a high genetic similarity among Mediterranean populations, distinguishing them from Sub-Saharan African and Asian populations. The Fst comparative analysis identified 27 variants exhibiting significant differentiation between the studied populations. Among these variants, four SNPs rs622342, rs3846662, rs7294, rs5215 located in SLC22A1, HMGCR, VKORC1 and KCNJ11 genes respectively, are reported to be associated with ethnic variability in drug responses. In conclusion, correlating the frequencies of genotype risk variants with their associated ADRs would enhance drug outcomes and the implementation of personalized medicine in the studied populations.

The African Human Microbiome Portal: a public web portal of curated metagenomic metadata.

There is growing evidence that comprehensive and harmonized metadata are fundamental for effective public data reusability. However, it is often challenging to extract accurate metadata from public repositories. Of particular concern is the metagenomic data related to African individuals, which often omit important information about the particular features of these populations. As part of a collaborative consortium, H3ABioNet, we created a web portal, namely the African Human Microbiome Portal (AHMP), exclusively dedicated to metadata related to African human microbiome samples. Metadata were collected from various public repositories prior to cleaning, curation and harmonization according to a pre-established guideline and using ontology terms. These metadata sets can be accessed at https://microbiome.h3abionet.org/. This web portal is open access and offers an interactive visualization of 14 889 records from 70 bioprojects associated with 72 peer reviewed research articles. It also offers the ability to download harmonized metadata according to the user's applied filters. The AHMP thereby supports metadata search and retrieve operations, facilitating, thus, access to relevant studies linked to the African Human microbiome. Database URL:  https://microbiome.h3abionet.org/.

Genetic landscape of forensic DNA phenotyping markers among Mediterranean populations.

Forensic DNA Phenotyping can reveal the appearance of an unknown individual by predicting the External Visible Characteristics (EVC) from DNA obtained at the crime scene. Our aim is to characterize the genetic landscape of Human identification markers responsible for EVC among Mediterranean populations compared to other worldwide groups. We conducted an exhaustive search for genes involved in EVC variation. Then, variants located on these genes were extracted from public genotypic data of Mediterranean, American, African and East Asiatic populations. The genetic landscape of these Human identification markers, their allelic distribution and admixture analyses, were determined using plink, R and ADMIXTURE softwares. Our results showed that the Mediterranean populations appear close to the Mexican populations and distinguished from sub Saharan African populations living in the USA and from East Asiatic populations. We highlighted a total of 103454 common variants shared between the studied populations and among them, 25 common variants associated with EVC. Interestingly, genotype frequencies results showed that the rs17646946, rs13016869, rs977588, rs1805008 and rs2240751 variants located respectively in the TCHH, PRKCE, OCA2, MC1R and MFSD12 genes are significantly different between the Mediterranean and Asiatic populations. The genotype frequencies of the variants rs977589 and rs7179994 located in the OCA2 gene, and of rs12913832 and rs2240751 located respectively in HERC2 and MFSD12 genes are significantly different between the Mediterranean and American populations. Our work generates a large number of EVC variants that could be a valuable resource for future studies in the forensic field.

Case report: Exome sequencing revealed disease-causing variants in a patient with spondylospinal thoracic dysostosis.

Background: Spondylocostal dysostosis is a rare genetic disorder caused by mutations in DLL3, MESP2, LFNG, HES7, TBX6, and RIPPLY2. A particular form of this disorder characterized by the association of spondylocostal dysostosis with multiple pterygia has been reported and called spondylospinal thoracic dysostosis. Both disorders affect the spine and ribs, leading to abnormal development of the spine. Spondylospinal thoracic dysostosis is a rare syndrome characterized by the association of multiple vertebral segmentation defects, thoracic cage deformity, and multiple pterygia. This syndrome can be considered a different form of the described spondylocostal dysostosis. However, no genetic testing has been conducted for this rare disorder so far. Methods: We report here the case of an 18-month-old female patient presenting the clinical and radiological features of spondylospinal thoracic dysostosis. To determine the underlying genetic etiology, whole exome sequencing (WES) and Sanger sequencing were performed. Results: Using WES, we identified a variant in the TPM2 gene c. 628C>T, already reported in the non-lethal form of multiple pterygium syndrome. In addition, following the analysis of WES data, using bioinformatic tools, for oligogenic diseases, we identified candidate modifier genes, CAP2 and ADCY6, that could impact the clinical manifestations. Conclusion: We showed a potential association between TPM2 and the uncommon spondylocostal dysostosis phenotype that would require further validation on larger cohort.

Gut microbiota profile and the influence of nutritional status on bacterial distribution in diabetic and healthy Tunisian subjects.

Gut microbiota plays a key role in the regulation of metabolism and immunity. We investigated the profile of gut microbiota and the impact of dietary intake on gut bacterial distribution in diabetic and healthy Tunisian subjects, aiming to identify a dysbiotic condition, hence opening the way to restore eubiosis and facilitate return to health. In the present research, we enrolled 10 type 1 diabetic (T1D), 10 type 2 diabetic (T2D) patients and 13 healthy (H) subjects. Illumina Miseq technology was used to sequence V3-V4 hypervariable regions of bacterial 16SrRNA gene. Data were analyzed referring to QIIME 2 pipeline. RStudio software was used to explore the role of nutrition in gut bacterial distribution. At the phylum level, we identified an imbalanced gut microbiota composition in diabetic patients marked by a decrease in the proportion of Firmicutes and an increase in the abundance of Bacteroidetes compared with H subjects. We observed higher amounts of Fusobacteria and a decline in the levels of TM7 phyla in T1D patients compared with H subjects. However, we revealed a decrease in the proportions of Verrucomicrobia in T2D patients compared with H subjects. At the genus level, T2D subjects were more affected by gut microbiota alteration, showing a reduction in the relative abundance of Faecalibacterium, Akkermansia, Clostridium, Blautia and Oscillibacter, whereas T1D group shows a decrease in the proportion of Blautia. The gut bacteria distribution was mainly affected by fats and carbohydrates consumption. Gut microbiota composition was altered in Tunisian diabetic patients and affected by dietary habits.

Prevalence and risk factors of diabetes mellitus and hypertension in North East Tunisia calling for efficient and effective actions.

Diabetes and hypertension are a serious public health problem worldwide. In the last decades, prevalence of these two metabolic diseases has dramatically increased in the Middle East and North Africa region, especially in Tunisia. This study aimed to determine the prevalence of type 2 diabetes (T2D) and High Blood Pressure (HBP) in Zaghouan, a North-East region of Tunisia. To this end, an exploratory study with stratified random sampling of 420 participants has been carried out. Various data were collected. Blood samples and urine were drawn for biochemical assay. Then, all data were analyzed using the statistical R software. Results showed an alarming situation with an inter-regional difference in prevalence of obesity (50.0%, CI 95.0%), HBP (39.0%, CI 95.0%) and T2D (32.0%, CI 95.0%). This study allowed the discovery of 24, 17 and 2 new cases of T2D, HBP and T2D&HBP respectively. The association of some socio-economic factors and biochemical parameters with these chronic diseases has been highlighted. To conclude, the health situation in the governorate of Zaghouan requires urgent interventions to better manage the growing epidemic of non-communicable diseases (NCD) in the region. This study demonstrated the importance of engaging health policy makers in road mapping and implementing national NCD prevention programs.

Decoding the genetic relationship between Alzheimer's disease and type 2 diabetes: potential risk variants and future direction for North Africa.

Introduction: Alzheimer's disease (AD) and Type 2 diabetes (T2D) are both age-associated diseases. Identification of shared genes could help develop early diagnosis and preventive strategies. Although genetic background plays a crucial role in these diseases, we noticed an underrepresentation tendency of North African populations in omics studies. Materials and methods: First, we conducted a comprehensive review of genes and pathways shared between T2D and AD through PubMed. Then, the function of the identified genes and variants was investigated using annotation tools including PolyPhen2, RegulomeDB, and miRdSNP. Pathways enrichment analyses were performed with g:Profiler and EnrichmentMap. Next, we analyzed variant distributions in 16 worldwide populations using PLINK2, R, and STRUCTURE software. Finally, we performed an inter-ethnic comparison based on the minor allele frequency of T2D-AD common variants. Results: A total of 59 eligible papers were included in our study. We found 231 variants and 363 genes shared between T2D and AD. Variant annotation revealed six single nucleotide polymorphisms (SNP) with a high pathogenic score, three SNPs with regulatory effects on the brain, and six SNPs with potential effects on miRNA-binding sites. The miRNAs affected were implicated in T2D, insulin signaling pathways, and AD. Moreover, replicated genes were significantly enriched in pathways related to plasma protein binding, positive regulation of amyloid fibril deposition, microglia activation, and cholesterol metabolism. Multidimensional screening performed based on the 363 shared genes showed that main North African populations are clustered together and are divergent from other worldwide populations. Interestingly, our results showed that 49 SNP associated with T2D and AD were present in North African populations. Among them, 11 variants located in DNM3, CFH, PPARG, ROHA, AGER, CLU, BDNF1, CST9, and PLCG1 genes display significant differences in risk allele frequencies between North African and other populations. Conclusion: Our study highlighted the complexity and the unique molecular architecture of North African populations regarding T2D-AD shared genes. In conclusion, we emphasize the importance of T2D-AD shared genes and ethnicity-specific investigation studies for a better understanding of the link behind these diseases and to develop accurate diagnoses using personalized genetic biomarkers.

The first exome wide association study in Tunisia: identification of candidate loci and pathways with biological relevance for type 2 diabetes.

Introduction: Type 2 diabetes (T2D) is a multifactorial disease involving genetic and environmental components. Several genome-wide association studies (GWAS) have been conducted to decipher potential genetic aberrations promoting the onset of this metabolic disorder. These GWAS have identified over 400 associated variants, mostly in the intronic or intergenic regions. Recently, a growing number of exome genotyping or exome sequencing experiments have identified coding variants associated with T2D. Such studies were mainly conducted in European populations, and the few candidate-gene replication studies in North African populations revealed inconsistent results. In the present study, we aimed to discover the coding genetic etiology of T2D in the Tunisian population. Methods: We carried out a pilot Exome Wide Association Study (EWAS) on 50 Tunisian individuals. Single variant analysis was performed as implemented in PLINK on potentially deleterious coding variants. Subsequently, we applied gene-based and gene-set analyses using MAGMA software to identify genes and pathways associated with T2D. Potential signals were further replicated in an existing large in-silico dataset, involving up to 177116 European individuals. Results: Our analysis revealed, for the first time, promising associations between T2D and variations in MYORG gene, implicated in the skeletal muscle fiber development. Gene-set analysis identified two candidate pathways having nominal associations with T2D in our study samples, namely the positive regulation of neuron apoptotic process and the regulation of mucus secretion. These two pathways are implicated in the neurogenerative alterations and in the inflammatory mechanisms of metabolic diseases. In addition, replication analysis revealed nominal associations of the regulation of beta-cell development and the regulation of peptidase activity pathways with T2D, both in the Tunisian subjects and in the European in-silico dataset. Conclusions: The present study is the first EWAS to investigate the impact of single genetic variants and their aggregate effects on T2D risk in Africa. The promising disease markers, revealed by our pilot EWAS, will promote the understanding of the T2D pathophysiology in North Africa as well as the discovery of potential treatments.

Whole-exome sequencing reveals novel variants of monogenic diabetes in Tunisia: impact on diagnosis and healthcare management.

Introduction: Monogenic diabetes (MD) accounts for 3%-6% of all cases of diabetes. This prevalence is underestimated due to its overlapping clinical features with type 1 and type 2 diabetes. Hence, genetic testing is the most appropriate tool for obtaining an accurate diagnosis. In Tunisia, few cohorts of MD have been investigated until now. The aim of this study is to search for pathogenic variants among 11 patients suspected of having MD in Tunisia using whole-exome sequencing (WES). Materials and methods: WES was performed in 11 diabetic patients recruited from a collaborating medical center. The pathogenicity of genetic variation was assessed using combined filtering and bioinformatics prediction tools. The online ORVAL tool was used to predict the likelihood of combinations of pathogenic variations. Then, Sanger sequencing was carried out to confirm likely pathogenic predicted variants among patients and to check for familial segregation. Finally, for some variants, we performed structural modeling to study their impact on protein function. Results: We identified novel variants related to MD in Tunisia. Pathogenic variants are located in several MODY and non-MODY genes. We highlighted the presence of syndromic forms of diabetes, including the Bardet-Biedl syndrome, Alström syndrome, and severe insulin resistance, as well as the presence of isolated diabetes with significantly reduced penetrance for Wolfram syndrome-related features. Idiopathic type 1 diabetes was also identified in one patient. Conclusion: In this study, we emphasized the importance of genetic screening for MD in patients with a familial history of diabetes, mainly among admixed and under-represented populations living in low- and middle-income countries. An accurate diagnosis with molecular investigation of MD may improve the therapeutic choice for better management of patients and their families. Additional research and rigorous investigations are required to better understand the physiopathological mechanisms of MD and implement efficient therapies that take into account genomic context and other related factors.

Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing.

Introduction: Inherited mitochondrial diseases are the most common group of metabolic disorders caused by a defect in oxidative phosphorylation. They are characterized by a wide clinical and genetic spectrum and can manifest at any age. In this study, we established novel phenotype-genotype correlations between the clinical and molecular features of a cohort of Tunisian patients with mitochondrial diseases. Materials and methods: Whole-exome sequencing was performed on five Tunisian patients with suspected mitochondrial diseases. Then, a combination of filtering and bioinformatics prediction tools was utilized to assess the pathogenicity of genetic variations. Sanger sequencing was subsequently performed to confirm the presence of potential deleterious variants in the patients and verify their segregation within families. Structural modeling was conducted to study the effect of novel variants on the protein structure. Results: We identified two novel homozygous variants in NDUFAF5 (c.827G>C; p.Arg276Pro) and FASTKD2 (c.496_497del; p.Leu166GlufsTer2) associated with a severe clinical form of Leigh and Leigh-like syndromes, respectively. Our results further disclosed two variants unreported in North Africa, in GFM2 (c.569G>A; p.Arg190Gln) and FOXRED1 (c.1261G>A; p.Val421Met) genes, and we described the first case of fumaric aciduria in a Tunisian patient harboring the c.1358T>C; p.Leu453Pro FH variant. Conclusion: Our study expands the mutational and phenotypic spectrum of mitochondrial diseases in Tunisia and highlights the importance of next-generation sequencing to decipher the pathomolecular mechanisms responsible for these disorders in an admixed population.

Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment.

Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of the present study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS. Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next-generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations. A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1. Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations.

The Role of Dietary Intake in Type 2 Diabetes Mellitus: Importance of Macro and Micronutrients in Glucose Homeostasis.

The prevalence of Type 2 diabetes (T2D) is increasing worldwide. Genetics and lifestyle, especially diet, are contributing factors. Analyses of macro- and micronutrient intake across global populations may help to explain their impact on glucose homeostasis and disease development. To this end, 420 Tunisians were enrolled in a prospective cross-sectional study of daily food consumption. Various data were collected and blood samples were drawn for biochemical assay. A 24-h recall questionnaire was obtained from participants to evaluate dietary intake. Statistical analyses were conducted using Nutrilog and R software. Biochemical analyses stratified the studied population (n = 371) into three groups: diabetics (n = 106), prediabetics (n = 192) and controls (n = 73); 49 subjects were excluded. Our results showed that Tunisians had hypercaloric diets high in carbohydrates and fat with variability in the levels of some vitamins and minerals, including riboflavin and niacin, that were statistically different among groups. The lower intake of vitamin D was associated with a greater risk of T2D. Higher vitamin A and sodium intake were associated with poor glucose homeostasis, although protein intake may improve it. In perspective, nutrigenomic studies can provide insight into problematic diets and poor eating habits and offer opportunities to analyze the effects of behavioral changes that can mitigate T2D development and progression.

Molecular Epidemiology of SARS-CoV-2 in Tunisia (North Africa) through Several Successive Waves of COVID-19.

Documenting the circulation dynamics of SARS-CoV-2 variants in different regions of the world is crucial for monitoring virus transmission worldwide and contributing to global efforts towards combating the pandemic. Tunisia has experienced several waves of COVID-19 with a significant number of infections and deaths. The present study provides genetic information on the different lineages of SARS-CoV-2 that circulated in Tunisia over 17 months. Lineages were assigned for 1359 samples using whole-genome sequencing, partial S gene sequencing and variant-specific real-time RT-PCR tests. Forty-eight different lineages of SARS-CoV-2 were identified, including variants of concern (VOCs), variants of interest (VOIs) and variants under monitoring (VUMs), particularly Alpha, Beta, Delta, A.27, Zeta and Eta. The first wave, limited to imported and import-related cases, was characterized by a small number of positive samples and lineages. During the second wave, a large number of lineages were detected; the third wave was marked by the predominance of the Alpha VOC, and the fourth wave was characterized by the predominance of the Delta VOC. This study adds new genomic data to the global context of COVID-19, particularly from the North African region, and highlights the importance of the timely molecular characterization of circulating strains.

African Genomic Medicine Portal: A Web Portal for Biomedical Applications.

Genomics data are currently being produced at unprecedented rates, resulting in increased knowledge discovery and submission to public data repositories. Despite these advances, genomic information on African-ancestry populations remains significantly low compared with European- and Asian-ancestry populations. This information is typically segmented across several different biomedical data repositories, which often lack sufficient fine-grained structure and annotation to account for the diversity of African populations, leading to many challenges related to the retrieval, representation and findability of such information. To overcome these challenges, we developed the African Genomic Medicine Portal (AGMP), a database that contains metadata on genomic medicine studies conducted on African-ancestry populations. The metadata is curated from two public databases related to genomic medicine, PharmGKB and DisGeNET. The metadata retrieved from these source databases were limited to genomic variants that were associated with disease aetiology or treatment in the context of African-ancestry populations. Over 2000 variants relevant to populations of African ancestry were retrieved. Subsequently, domain experts curated and annotated additional information associated with the studies that reported the variants, including geographical origin, ethnolinguistic group, level of association significance and other relevant study information, such as study design and sample size, where available. The AGMP functions as a dedicated resource through which to access African-specific information on genomics as applied to health research, through querying variants, genes, diseases and drugs. The portal and its corresponding technical documentation, implementation code and content are publicly available.

Association of HNF1A gene variants and haplotypes with metabolic syndrome: a case-control study in the Tunisian population and a meta-analysis.

BACKGROUND: Variants in the Hepatocyte Nuclear Factor 1 Alpha gene (HNF1A) are associated with lipoproteins levels and type 2 diabetes. In this study, we aimed to assess the association of HNF1A gene and haplotypes with the metabolic syndrome (MetS) and its components through an association study in the Tunisian population as well as by a meta-analysis. METHODS: A total of 594 Tunisian individuals were genotyped for three variants (rs1169288, rs2464196 and rs735396) located in HNF1A gene using KASPar technology. Statistical analyses were performed with R software. The association was furthermore evaluated through a meta-analysis of our results with those obtained in a Moroccan population. RESULTS: Our results showed no association between HNF1A variants and MetS in the Tunisian population. However, a significant association was observed between the variant rs735396 and a higher waist circumference. The stratified analysis according to the sex highlighted a significant association between the variant rs1169288 and high cholesterol levels only in women. Similarly, Haplotype analysis showed an association between the HNF1A minor haplotype and high total cholesterol mainly in women. Finally, our meta-analysis showed no association between HNF1A variants and MetS. CONCLUSIONS: Our findings exclude the involvement of the three HNF1A variants rs1169288, rs2464196 and rs735396 in the susceptibility to MetS in our studied Tunisian population but emphasize the role of these variants in the cholesterol homeostasis with sex-specific differences, which may serve to rise clinical consideration to early statin therapy in women carrying these genetic variants.

Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.

Multiallelic Rare Variants in BBS Genes Support an Oligogenic Ciliopathy in a Non-obese Juvenile-Onset Syndromic Diabetic Patient: A Case Report.

Juvenile-onset diabetes may occur in the context of a rare syndromic presentation, suggesting a monogenic etiology rather than a common multifactorial diabetes. In the present study, we report the case of a young diabetic Tunisian patient presenting learning problems, speech deficits, short stature, brachydactyly, and a normal weight. Whole exome sequencing analysis revealed five heterozygous genetic variants in BBS1, BBS4, BBS8, MKS1, and CEP290. These genes are involved in the regulation of cilium biogenesis and function. We analyzed variant combinations pathogenicity using the recently developed ORVAL tool, and we hypothesized that cumulative synergetic effects of these variants could explain the syndromic phenotype observed in our patient. Therefore, our investigation suggested a genetic diagnosis of Bardet-Biedl syndrome with an oligogenic inheritance pattern rather than a monogenic diabetes. Although there is no curative therapy for this ciliopathy at the moment, a genetic diagnosis may offer other supportive care options, including the prevention of other possible clinical manifestations of this syndrome, mainly renal abnormalities, obesity, liver fibrosis, and hypertension, as well as the genetic counseling for family members.

A map of copy number variations in the Tunisian population: a valuable tool for medical genomics in North Africa.

Copy number variation (CNV) is considered as the most frequent type of structural variation in the human genome. Some CNVs can act on human phenotype diversity, encompassing rare Mendelian diseases and genomic disorders. The North African populations remain underrepresented in public genetic databases in terms of single-nucleotide variants as well as for larger genomic mutations. In this study, we present the first CNV map for a North African population using the Affymetrix Genome-Wide SNP (single-nucleotide polymorphism) array 6.0 array genotyping intensity data to call CNVs in 102 Tunisian healthy individuals. Two softwares, PennCNV and Birdsuite, were used to call CNVs in order to provide reliable data. Subsequent bioinformatic analyses were performed to explore their features and patterns. The CNV map of the Tunisian population includes 1083 CNVs spanning 61.443 Mb of the genome. The CNV length ranged from 1.017 kb to 2.074 Mb with an average of 56.734 kb. Deletions represent 57.43% of the identified CNVs, while duplications and the mixed loci are less represented. One hundred and three genes disrupted by CNVs are reported to cause 155 Mendelian diseases/phenotypes. Drug response genes were also reported to be affected by CNVs. Data on genes overlapped by deletions and duplications segments and the sequence properties in and around them also provided insights into the functional and health impacts of CNVs. These findings represent valuable clues to genetic diversity and personalized medicine in the Tunisian population as well as in the ethnically similar populations from North Africa.

Association of rs662799 variant and APOA5 gene haplotypes with metabolic syndrome and its components: a meta-analysis in North Africa.

Apolipoprotein A5 (APOA5) has been linked to metabolic syndrome (MetS) in several populations. In North Africa, only the Tunisian and Moroccan populations were investigated. Our aim is to assess the association between APOA5 gene variant (rs662799) and haplotypes with MetS in Tunisian population and to perform a meta-analysis in North Africa. A total of 594 Tunisian participants were genotyped for polymorphism rs662799 using KASPar technology. Two polymorphisms rs3135506 and rs651821 in APOA5 gene genotyped in our previous study, were used in addition to rs662799 to assess the haplotype association with MetS. The genotype of 875 participants was used for the meta-analysis. Statistical analyses were performed with R software. The rs662799 increases the risk of MetS under the dominant (P=0.018) and the additive models (P=0.028) in the Tunisian population. After stratification of the cohort following the sex and the geographic origin, a positive association of rs662799 with MetS was found for participant from the Northern region and for the women group. Only the haplotype AGT showed a significant association with MetS by decreasing the risk of the disease. The meta-analysis reported a significant association of rs662799 and rs3135506 with MetS. Our results showed a significant association between the APOA5 gene variants rs662799 and haplotypes with MetS and its traits in Tunisia. An impact of the sex and the geographic origin on the genotype distribution was highlighted. Our funding emphasizes the role of APOA5 in the development of MetS in North Africa.

A review of clinical pharmacogenetics Studies in African populations.

Effective interventions and treatments for complex diseases have been implemented globally, however, coverage in Africa has been comparatively lower due to lack of capacity, clinical applicability and knowledge on the genetic contribution to disease and treatment. Currently, there is a scarcity of genetic data on African populations, which have enormous genetic diversity. Pharmacogenomics studies have the potential to revolutionise treatment of diseases, therefore, African populations are likely to benefit from these approaches to identify likely responders, reduce adverse side effects and optimise drug dosing. This review discusses clinical pharmacogenetics studies conducted in African populations, focusing on studies that examined drug response in complex diseases relevant to healthcare. Several pharmacogenetics associations have emerged from African studies, as have gaps in knowledge.