Pharmacogenetic landscape of pain management variants among Mediterranean populations.

Background: Chronic pain is a major socioeconomic burden in the Mediterranean region. However, we noticed an under-representation of these populations in the pharmacogenetics of pain management studies. In this context, we aimed 1) to decipher the pharmacogenetic variant landscape among Mediterranean populations compared to worldwide populations in order to identify therapeutic biomarkers for personalized pain management and 2) to better understand the biological process of pain management through in silico investigation of pharmacogenes pathways. Materials and Methods: We collected genes and variants implicated in pain response using the Prisma guidelines from literature and PharmGK database. Next, we extracted these genes from genotyping data of 829 individuals. Then, we determined the variant distribution among the studied populations using multivariate (MDS) and admixture analysis with R and STRUCTURE software. We conducted a Chi2 test to compare the interethnic frequencies of the identified variants. We used SNPinfo web server, miRdSNP database to identify miRNA-binding sites. In addition, we investigated the functions of the identified genes and variants using pathway enrichment analysis and annotation tools. Finally, we performed docking analysis to assess the impact of variations on drug interactions. Results: We identified 63 variants implicated in pain management. MDS analysis revealed that Mediterranean populations are genetically similar to Mexican populations and divergent from other populations. STRUCTURE analysis showed that Mediterranean populations are mainly composed of European ancestry. We highlighted differences in the minor allele frequencies of three variants (rs633, rs4680, and rs165728) located in the COMT gene. Moreover, variant annotation revealed ten variants with potential miRNA-binding sites. Finally, protein structure and docking analysis revealed that two missense variants (rs4680 and rs6267) induced a decrease in COMT protein activity and affinity for dopamine. Conclusion: Our findings revealed that Mediterranean populations diverge from other ethnic groups. Furthermore, we emphasize the importance of pain-related pathways and miRNAs to better implement these markers as predictors of analgesic responses in the Mediterranean region.

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.

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.

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.