Association Between Angiotensinogen Gene M235T and Renin–Angiotensin System Insertion/Deletion Variants and Risk of Cardiovascular Disease in North African and Middle Eastern Populations: A Systematic Review and Meta-Analysis

Despite its key location for population movements out of and back into Africa, Yemen has not yet been sampled on a regional level for an investigation of sub-Saharan, West Eurasian, and South Asian genetic contributions. In this study, we present mitochondrial DNA (mtDNA) data for regionally distinct Yemeni populations that reveal different distributions of mtDNA lineages. An extensive database of mtDNA sequences from North and East African, Middle Eastern and Indian populations was analyzed to provide a context for the regional Yemeni mtDNA datasets. The groups of western Yemen appear to be most closely related to Middle Eastern and North African populations, while the eastern Yemeni population from Hadramawt is most closely related to East Africa. Furthermore, haplotype matches with Africa are almost exclusively confined to West Eurasian R0a haplogroup in southwestern Yemen, although more sub-Saharan L-type matches appear in more northern Yemeni populations. In fact, Yemeni populations have the highest frequency of R0a haplotypes detected to date, thus Yemen or southern Arabia may be the site of the initial expansion of this haplogroup. Whereas two variants of the sub-Saharan haplogroup M1 were detected only in southwestern Yemen close to the Bab el-Mandeb Strait, different non-African M haplotypes were detected at low frequencies (approximately 2%) in western parts of the country and at a higher frequency (7.5%) in the Hadramawt. We conclude that the Yemeni gene pool is highly stratified both regionally and temporally and that it has received West Eurasian, Northeast African, and South Asian gene flow.

Germ-line mutations in BRCA1 breast cancer susceptibility gene account for a large proportion of hereditary breast cancer families and show considerable ethnic and geographical variations. The contribution of BRCA1 mutations to hereditary breast cancer has not yet been thoroughly investigated in Middle Eastern and North African populations. In this study, 16 Tunisian high-risk breast cancer families were screened for germline mutations in the entire BRCA1 coding region and exon–intron boundaries using direct sequencing. Six families were found to carry BRCA1 mutations with a prevalence of 37.5%. Four different deleterious mutations were detected. Three truncating mutations were previously described: c.798_799delTT (916 delTT), c.3331_3334delCAAG (3450 delCAAG), c.5266dupC (5382 insC) and one splice site mutation which seems to be specific to the Tunisian population: c.212 + 2insG (IVS5 + 2insG). We also identified 15 variants of unknown clinical significance. The c.798_799delTT mutation occurred at an 18% frequency and was shared by three apparently unrelated families. Analyzing five microsatellite markers in and flanking the BRCA1 locus showed a common haplotype associated with this mutation. This suggests that the c.798_799delTT mutation is a Tunisian founder mutation. Our findings indicate that the Tunisian population has a spectrum of prevalent BRCA1 mutations, some of which appear as recurrent and founding mutations.

The Souss, located in southern Morocco, is one of the oldest areas of human settlement in North Africa. Despite this historical relevance, the Souss has not received sufficient attention in terms of population genetic studies. In this study, we utilized the AmpFlSTR Identifiler PCR amplification system to establish the allelic frequencies and statistical parameters of 15 autosomal STRs (Short Tandem Repeats) in 150 healthy unrelated Berber-speaking individuals from the Souss. We explored the genetic relationships between Souss and other reference populations based on our dataset as well as previously published population data. A total of 210 alleles were detected with corresponding allele frequencies ranging from 0.003 to 0.367. The most polymorphic locus was D18S51 with 23 alleles which was also the most discriminating locus as expected. The phylogenetic analysis clustered the Souss closer to the Azrou and southern Moroccan populations. The population comparison showed affinity between the Souss and most North African populations, as well as with Middle Easterners and Europeans. Historical events and geographical proximity have contributed to the affinity between the Souss and surrounding North African, Southern European, and Middle Eastern populations. Overall, this study highlights the reliability of the 15 STRs for identifying individuals and assessing paternity in the Souss population.

Background: Recent genomic analyses suggest that the current North African gene pool was mainly influenced by population flow coming from the East that altered the genetic structure of autochthonous Berber populations. Such genetic flow has not been extensively addressed yet using North African populations of Middle-eastern origin as reference.Aim: To discern the Middle-eastern component in the genetic background of Tunisian Arabs and evaluate the extent of gene flow from the Middle East into North African autochthonous Berber populations.Subjects and methods: This study has examined 113 Tunisians of well-known Arabian origin from Kairouan region, using 15 autosomal Short Tandem Repeats (STRs) loci.Results: No deviations from Hardy-Weinberg equilibrium were observed and all loci presented high levels of heterozygosity. Principal coordinate and STRUCTURE analyses were consistent in clustering together North African and Middle Eastern populations, likely reflecting the recent gene flow from the East dating back to the Arab conquest period. This demographic migration and the Arabisation process that submerged the original Berber language and customs seems to have be accompanied by substantial gene flow and genetic admixture.Conclusion: This study represents an additional step to obtain a comprehensive understanding of the complex demographic history of North African populations.

The geographic location of Egypt, at the interface between North Africa, the Middle East, and southern Europe, prompted us to investigate the genetic diversity of this population and its relationship with neighboring populations. To assess the extent to which the modern Egyptian population reflects this intermediate geographic position, ten Unique Event Polymorphisms (UEPs), mapping to the nonrecombining portion of the Y chromosome, have been typed in 164 Y chromosomes from three North African populations. The analysis of these binary markers, which define 11 Y-chromosome lineages, were used to determine the haplogroup frequencies in Egyptians, Moroccan Arabs, and Moroccan Berbers and thereby define the Y-chromosome background in these regions. Pairwise comparisons with a set of 15 different populations from neighboring European, North African, and Middle Eastern populations and geographic analysis showed the absence of any significant genetic barrier in the eastern part of the Mediterranean area, suggesting that genetic variation and gene flow in this area follow the "isolation-by-distance" model. These results are in sharp contrast with the observation of a strong north-south genetic barrier in the western Mediterranean basin, defined by the Gibraltar Strait. Thus, the Y-chromosome gene pool in the modern Egyptian population reflects a mixture of European, Middle Eastern, and African characteristics, highlighting the importance of ancient and recent migration waves, followed by gene flow, in the region.

This article aims to take stock of knowledge on the history of the human settlement of North Africa and the genetic history of Algerians within North African populations by gathering the most important published results related to HLA allele analysis. These results revealed a strong genetic relationship between studied North African populations (Algeria, Morocco and Tunisia). Such evident genetic affinity between North African populations, also proved by the use of other powerful autosomal markers, agrees with historic data considering North African populations as having similar origins. HLA allele analysis also indicated a genetic link between North African populations (Algeria, Tunisia and Morocco) and the populations of the South-Western Europe particularly the Basques and Spaniards. This would reflect a Neolithic relationship between Iberians and the natives of North Africa (the Berbers). However, other results showed a genetic distinction between samples from North African populations and Middle Eastern populations (Arab-Palestinians, Lebanese’s and Jordanians). Beside these results related to Mediterranean populations, the HLA allele variation was analyzed at the world scale showing low genetic differentiations among the three broad continental areas, with no special divergence of Africa.
 Keywords: Genetic diversity; Molecular Anthropology; Genetic History; HLA genes; North Africa; Algeria

Inclusion of Middle Eastern and North African populations in diabetes clinical research

In the Limelight: December 2021

Morphological and biochemical divergence between Spanish and Moroccan populations of Lacerta lepida demonstrate that these populations are not conspecific; Iberian populations are referred to Lacerta lepida, Moroccan populations to L. pater. An evolutionary scenario, consistent with the biochemical and morphological data, is inferred from the physiographic history of the region. Lacerta lepida inhabits the Iberian pen- insula, France, N.W. Italy, and North Af- rica; the subspecies L. 1. lepida is restricted to Europe, L. I. pater to North Africa (Bou- lenger, 1887; Bischoff et al., 1984). Artifi- cially hybridized specimens drawn from Spanish and Tunisian populations have been shown to exhibit reduced fertility, however, and it has been suggested that North African and European populations be considered separate species (Bischoff, 1982). I was curious to know to what de- gree, if at all, this indication of genetic independence between European and North African populations might be con- firmed through data gathered by standard systematic methods. Electrophoretic, micro-complement fix- ation, and morphological analysis revealed substantial differentiation between Span- ish and Moroccan populations and con- firmed that European and North African populations are not conspecific. The data supporting this conclusion are presented in the following pages, along with an in- ferred reconstruction of the evoutionary history of Iberian and Moroccan popula- tions.

The Garamantes flourished in southwestern Libya, in the core of the Sahara Desert ~3,000 years ago and largely controlled trans-Saharan trade. Their biological affinities to other North African populations, including the Egyptian, Algerian, Tunisian and Sudanese, roughly contemporary to them, are examined by means of cranial nonmetric traits using the Mean Measure of Divergence and Mahalanobis D(2) distance. The aim is to shed light on the extent to which the Sahara Desert inhibited extensive population movements and gene flow. Our results show that the Garamantes possess distant affinities to their neighbors. This relationship may be due to the Central Sahara forming a barrier among groups, despite the archaeological evidence for extended networks of contact. The role of the Sahara as a barrier is further corroborated by the significant correlation between the Mahalanobis D(2) distance and geographic distance between the Garamantes and the other populations under study. In contrast, no clear pattern was observed when all North African populations were examined, indicating that there was no uniform gene flow in the region.

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.

Copyright © Polskie Towarzystwo Kardiologiczne INTRODUCTION The renin–angiotensin–aldosterone system (RAAS) is a central regulator of cardiovascular (CV) and renal function and plays a key role in the pathophysiology of various CV and renal diseases [1, 2]. The RAAS consists of a series of enzymatic reactions culminating in the generation of angiotensin II (Ang-II) in plasma and in various tissues, including the vessels, the heart and the kidney. Ang-II mediates most of the biological actions of RAAS through an interaction with two different types of G-protein coupled receptors — AT1 and AT2 — that can have opposing effects [1, 2]. The importance of Ang-II is supported by the widespread clinical use of angiotensin-converting enzyme (ACE) inhibitors in a wide array of CV and renal diseases. However, the RAAS is far more complex than previously understood, and several new aspects have been recently identified that have potential clinical implications. First, tissue Ang-II may be generated by non-ACE-mediated enzymes, particularly in several conditions associated with an increased CV disease risk (e.g. acute myocardial infarction [AMI]) [3]. Second, ACE can cleave and inactivate other peptides such as bradykinin, a family of potent vasodilators that counterbalance the effects of Ang-II. Importantly, all these mechanisms can be involved in the overall effects of drugs inhibiting RAAS and could help explain some aspects of the complexity of their therapeutic profile. Since their discovery more than 25 years ago, ACE inhibitors have been widely used for the treatment of CV diseases for their important cardioprotective and vasculoprotective properties [1–3]. Clinical data has demonstrated that ACE inhibitors are very effective at reducing blood pressure in a large proportion of patients with hypertension (HBP) [1, 2] when given alone or in combination. ACE inhibitors improve the clinical prognosis of patients with congestive heart failure (CHF) and AMI, particularly when complicated by overt left ventricular (LV) dysfunction [4], although their efficacy may be limited in postmyocardial patients with preserved LV function [5, 6]. ACE inhibitors are also the treatment of choice for many patients with types 1 and 2 diabetes, particularly when complicated by renal disease or proteinuria. Among the different ACE inhibitors, the efficacy of zofenopril has been proven in a wide population of patients with HBP and coronary heart disease, in particular AMI [4]. The clinical efficacy of zofenopril has been extensively studied in many subpopulations of high-risk patients where it has proven to be very effective, compared to both placebo and active treatments. Treatment with zofenopril is associated with a favourable tolerability profile as a consequence of its unique mechanism of action, which might also contribute to the additional benefits beyond ACE inhibition that have been described in patients treated with zofenopril.

Menopausal hormone treatment cardiovascular disease: another look at an unresolved conundrum

Novel data on the pathogenesis of atherosclerosis, treatment targets, and new therapeutic interventions in lipid-related cardiovascular risk factors.

Skin auto fluorescence (SAF) is used as a proxy for the accumulation of advanced glycation end products (AGEs) and has been proposed to stratify patients into cardiovascular disease (CVD) and diabetes mellitus (DM) risk groups. This study evaluates the effects of seven different ethnicities (Arab, Central-East African, Eastern Mediterranean, European, North African, South Asian and Southeast Asian) and gender on SAF as well as validating SAF assessment as a risk estimation tool for CVD and DM in an Arabian cohort. SAF data from self-reported healthy 2,780 individuals, collated from three independent studies, has been linear modelled using age and gender as a covariate. A cross-study harmonized effect size (Cohens’d) is provided for each ethnicity. Furthermore, new data has been collected from a clinically well-defined patient group of 235 individuals, to evaluate SAF as a clinical tool for DM and CVD-risk estimation in an Arab cohort. In an Arab population, SAF-based CVD and/or DM risk-estimation can be improved by referencing to ethnicity and gender-specific SAF values. Highest SAF values were observed for the North African population, followed by East Mediterranean, Arab, South Asian and European populations. The South Asian population had a slightly steeper slope in SAF values with age compared to other ethnic groups. All ethnic groups except Europeans showed a significant gender effect. When compared with a European group, effect size was highest for Eastern Mediterranean group and lowest for South Asian group. The Central-East African and Southeast Asian ethnicity matched closest to the Arab and Eastern Mediterranean ethnicities, respectively. Ethnic and gender-specific data improves performance in SAF-based CVD and DM risk estimation. The provided harmonized effect size allows a direct comparison of SAF in different ethnicities. For the first time, gender differences in SAF are described for North African and East Mediterranean populations.