scholarly journals The extent and impact of variation in ADME genes in sub-Saharan African populations

2020 ◽  
Author(s):  
Jorge da Rocha ◽  
Houcemeddine Othman ◽  
Gerrit Botha ◽  
Laura Cottino ◽  
David Twesigomwe ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Full Range ◽  
Copy Number Variations ◽  
High Coverage ◽  
Data Set ◽  
Asian Populations ◽  
Novel Variants ◽  
African Populations ◽  
Sub Saharan

AbstractInvestigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterising pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterised in European and Asian populations, but African populations are under-studied – which has implications for safe and effective drug use in Africa.The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations.Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterisation of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.Author summaryThe ADME genes are a group of genes that play a key role in absorption, distribution, metabolism and excretion of drugs. Variations in these genes can have a significant impact on drug safety and efficacy. Africa has a high level of genetic variation and is under-studied in drug development, which makes study of variations in these genes in African populations very important. Using a new data set of 458 high-coverage genomes from across Africa, we characterise the extent and impact of variation in the ADME genes, looking at both single nucleotide and copy number variations. We identified 343,368 variants, including 40,692 novel variants, and 930 coding variants which are predicted to have high impact on function. Our discovery curves indicate that there will be considerable value in sequencing more African genomes. Moreover, relatively few of these novel variants are captured on common genotyping arrays. We show that there is considerable diversity within Africa in some important genes, and this will have significant consequences for the emerging field of precision medicine in Africa.

scholarly journals The Extent and Impact of Variation in ADME Genes in Sub-Saharan African Populations

2021 ◽  
Vol 12 ◽  
Author(s):  
Jorge E. B. da Rocha ◽  
Houcemeddine Othman ◽  
Gerrit Botha ◽  
Laura Cottino ◽  
David Twesigomwe ◽  
...  
Keyword(s):  
Full Range ◽  
High Impact ◽  
African Population ◽  
High Coverage ◽  
Gene Variation ◽  
Research Bias ◽  
African Populations ◽  
Population Cluster ◽  
Sub Saharan ◽  
European Populations

Introduction: Investigating variation in genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs are key to characterizing pharmacogenomic (PGx) relationships. ADME gene variation is relatively well characterized in European and Asian populations, but data from African populations are under-studied—which has implications for drug safety and effective use in Africa.Results: We identified significant ADME gene variation in African populations using data from 458 high-coverage whole genome sequences, 412 of which are novel, and from previously available African sequences from the 1,000 Genomes Project. ADME variation was not uniform across African populations, particularly within high impact coding variation. Copy number variation was detected in 116 ADME genes, with equal ratios of duplications/deletions. We identified 930 potential high impact coding variants, of which most are discrete to a single African population cluster. Large frequency differences (i.e., >10%) were seen in common high impact variants between clusters. Several novel variants are predicted to have a significant impact on protein structure, but additional functional work is needed to confirm the outcome of these for PGx use. Most variants of known clinical outcome are rare in Africa compared to European populations, potentially reflecting a clinical PGx research bias to European populations.Discussion: The genetic diversity of ADME genes across sub-Saharan African populations is large. The Southern African population cluster is most distinct from that of far West Africa. PGx strategies based on European variants will be of limited use in African populations. Although established variants are important, PGx must take into account the full range of African variation. This work urges further characterization of variants in African populations including in vitro and in silico studies, and to consider the unique African ADME landscape when developing precision medicine guidelines and tools for African populations.

scholarly journals Single nucleotide polymorphism induces divergent dynamic patterns in CYP3A5: a microsecond scale biomolecular simulation of variants identified in Sub-Saharan African populations

2021 ◽  
Author(s):  
Houcemeddine Othman ◽  
Jorge Emanuel Batista da Rocha ◽  
Scott Hazelhurst
Keyword(s):  
Structural Changes ◽  
Rare Variants ◽  
Drug Binding ◽  
Sub Saharan Africa ◽  
High Coverage ◽  
Single Nucleotide ◽  
African Populations ◽  
Sub Saharan ◽  
Dynamics Simulations ◽  
The Impact

Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigates the impact of such variants on protein structure to assess their functional importance. We use genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype, and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability acts on the plasticity of the protein. The impact on drug binding may be drug dependant. We conclude that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.

scholarly journals Interleukin-6 receptor genetic variation and tocilizumab treatment response to COVID-19

2021 ◽  
Author(s):  
Ammar Ali Almarzooq
Keyword(s):  
Genetic Variation ◽  
Interleukin 6 ◽  
Treatment Efficacy ◽  
European Ancestry ◽  
Asian Populations ◽  
Inflammatory Conditions ◽  
African Populations ◽  
Interleukin 6 Receptor ◽  
Membrane Bound ◽  
Sub Saharan

ABSTRACTInterleukin-6 receptor (IL6R) stimulates the inflammatory pathways as part of the acute-phase response to infection. Tocilizumab is a monoclonal antibody that inhibits both membrane-bound and soluble IL6R and is used to treat inflammatory conditions, including COVID-19. Despite the disproportionate incidence of COVID-19 among underserved, racial, and ethnic minority populations, the efficacy of tocilizumab in hospitalized COVID-19 patients from these populations is unclear. In this work, three genetic markers for the IL6R gene were analyzed across diverse ethnic backgrounds to identify population differences in response to tocilizumab treatment. Genetic structure analyses showed that African populations were significantly different from other described populations. In addition, mapped frequencies of these alleles showed that Sub-Saharan African populations were 3.4x more likely to show an impaired response to tocilizumab than East Asian populations, and 1.8x more likely than European ancestry populations. Existing IL6R genotype results may identify populations at increased therapeutic failure risk. As results from current clinical trials on the efficacy of tocilizumab treatment for extreme COVID-19 infections are conflicting, more studies are needed across diverse patient backgrounds to better understand the genetic factors necessary to predict treatment efficacy. This work demonstrates how pharmacogenomics studies can elucidate genetic variation on treatment efficacy on COVID-19.

scholarly journals Single Nucleotide Polymorphism Induces Divergent Dynamic Patterns in CYP3A5: A Microsecond Scale Biomolecular Simulation of Variants Identified in Sub-Saharan African Populations

2021 ◽  
Vol 22 (15) ◽  
pp. 7786
Author(s):  
Houcemeddine Othman ◽  
Jorge E. B. da Rocha ◽  
Scott Hazelhurst
Keyword(s):  
Structural Changes ◽  
Rare Variants ◽  
Drug Binding ◽  
Sub Saharan Africa ◽  
High Coverage ◽  
Single Nucleotide ◽  
African Populations ◽  
Sub Saharan ◽  
Dynamics Simulations ◽  
The Impact

Pharmacogenomics aims to reveal variants associated with drug response phenotypes. Genes whose roles involve the absorption, distribution, metabolism, and excretion of drugs, are highly polymorphic between populations. High coverage whole genome sequencing showed that a large proportion of the variants for these genes are rare in African populations. This study investigated the impact of such variants on protein structure to assess their functional importance. We used genetic data of CYP3A5 from 458 individuals from sub-Saharan Africa to conduct a structural bioinformatics analysis. Five missense variants were modeled and microsecond scale molecular dynamics simulations were conducted for each, as well as for the CYP3A5 wildtype and the Y53C variant, which has a known deleterious impact on enzyme activity. The binding of ritonavir and artemether to CYP3A5 variant structures was also evaluated. Our results showed different conformational characteristics between all the variants. No significant structural changes were noticed. However, the genetic variability seemed to act on the plasticity of the protein. The impact on drug binding might be drug dependant. We concluded that rare variants hold relevance in determining the pharmacogenomics properties of populations. This could have a significant impact on precision medicine applications in sub-Saharan Africa.

scholarly journals Schistosoma mansoni eggs induce Wnt/β-catenin signaling and activate the protooncogene c-Jun in human and hamster colon

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jakob Weglage ◽  
Friederike Wolters ◽  
Laura Hehr ◽  
Jakob Lichtenberger ◽  
Celina Wulz ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Colorectal Carcinogenesis ◽  
Sub Saharan Africa ◽  
Interleukin 4 ◽  
Health Burden ◽  
Sub Saharan ◽  
Considerable Morbidity ◽  
First Time

AbstractSchistosomiasis (bilharzia) is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, with considerable morbidity in parts of the Middle East, South America, Southeast Asia, in sub-Saharan Africa, and particularly also in Europe. The WHO describes an increasing global health burden with more than 290 million people threatened by the disease and a potential to spread into regions with temperate climates like Corsica, France. The aim of our study was to investigate the influence of S. mansoni infection on colorectal carcinogenic signaling pathways in vivo and in vitro. S. mansoni infection, soluble egg antigens (SEA) and the Interleukin-4-inducing principle from S. mansoni eggs induce Wnt/β-catenin signaling and the protooncogene c-Jun as well as downstream factor Cyclin D1 and markers for DNA-damage, such as Parp1 and γH2a.x in enterocytes. The presence of these characteristic hallmarks of colorectal carcinogenesis was confirmed in colon biopsies from S. mansoni-infected patients demonstrating the clinical relevance of our findings. For the first time it was shown that S. mansoni SEA may be involved in the induction of colorectal carcinoma-associated signaling pathways.

scholarly journals Genome diversity in Ukraine

GigaScience ◽  
2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Taras K Oleksyk ◽  
Walter W Wolfsberger ◽  
Alexandra M Weber ◽  
Khrystyna Shchubelka ◽  
Olga T Oleksyk ◽  
...  
Keyword(s):  
Sequence Data ◽  
Copy Number Variations ◽  
Genomic Variation ◽  
High Coverage ◽  
Genome Data ◽  
New Information ◽  
Genome Wide ◽  
Public Data ◽  
Genome Wide Data ◽  
Multiple Samples

Abstract Background The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. Results The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population. Conclusions Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

scholarly journals Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes

2021 ◽  
Author(s):  
Silvia Martin-Almedina ◽  
Kazim Ogmen ◽  
Ege Sackey ◽  
Dionysios Grigoriadis ◽  
Christina Karapouliou ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Fetal Hydrops ◽  
Clinical Phenotypes ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Disease Mechanisms ◽  
Novel Variants ◽  
Uncertain Significance ◽  
Clinical Phenotyping

Abstract Purpose Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. Methods Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. Results Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype–genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. Conclusion This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.

scholarly journals A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program

2021 ◽  
Author(s):  
Adrienne M Stilp ◽  
Leslie S Emery ◽  
Jai G Broome ◽  
Erin J Buth ◽  
Alyna T Khan ◽  
...  
Keyword(s):  
Precision Medicine ◽  
Association Studies ◽  
Controlled Vocabulary ◽  
National Institutes Of Health ◽  
Design Data ◽  
Data Set ◽  
Data Repositories ◽  
Phenotype Data ◽  
National Heart Lung ◽  
Centralized System

Abstract Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute’s Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

scholarly journals National Culture and Africa Revisited: Ethnolinguistic Group Data From 35 African Countries

2019 ◽  
Vol 54 (1) ◽  
pp. 73-91 ◽  
Author(s):  
Bert van Pinxteren
Keyword(s):  
Survey Data ◽  
National Culture ◽  
Cultural Psychology ◽  
Sub Saharan Africa ◽  
African Countries ◽  
Data Set ◽  
Group Data ◽  
Sub Saharan ◽  
National Boundaries ◽  
Ethnolinguistic Group

Africa is a continent of considerable cultural diversity. This diversity does not necessarily run in parallel to the national boundaries that were created in Africa in the colonial period. However, decades of nation building in Africa must have made their mark. Is it possible nowadays to distinguish national cultures in Africa, or are the traditional ethnolinguistic distinctions more important? This article uses an approach developed in cross-cultural psychology to examine these questions. In 2012, Minkov and Hofstede published an article in this journal analyzing World Values Survey data from seven countries in Sub-Saharan Africa at the level of subnational administrative regions. They argued that national culture is also a meaningful concept in this region. This study reexamines the matter. It uses an innovative approach, looking at ethnolinguistic groups instead of at administrative regions and using the much more extensive Afrobarometer survey data set. It finds that although the Minkov/Hofstede study still has merit, the picture is more nuanced in several important ways. There is not one pattern that adequately describes the situation in the whole of Africa.1

scholarly journals Fluconazole MIC and the Fluconazole Dose/MIC Ratio Correlate with Therapeutic Response among Patients with Candidemia

2005 ◽  
Vol 49 (8) ◽  
pp. 3171-3177 ◽  
Author(s):  
Cornelius J. Clancy ◽  
Victor L. Yu ◽  
Arthur J. Morris ◽  
David R. Snydman ◽  
M. Hong Nguyen
Keyword(s):  
Therapeutic Response ◽  
Geometric Mean ◽  
Therapeutic Failure ◽  
Response To Therapy ◽  
Success Rates ◽  
Therapeutic Success ◽  
Data Set ◽  
In Vitro Susceptibility ◽  
Dose Dependent

ABSTRACT We tested 32 Candida isolates recovered in the early 1990s from the bloodstreams of patients with candidemia for in vitro susceptibility to fluconazole and determined if MIC and/or the daily dose of fluconazole/MIC ratio correlated with the response to therapy. This is a unique data set since 87.5% (28/32) of patients were treated with fluconazole doses now considered to be inadequate (≤200 mg), which contributed to high therapeutic failure rates (53% [17/32]). The geometric mean MIC and dose/MIC ratio for isolates associated with therapeutic failure (11.55 μg/ml and 14.3, respectively) differed significantly from values associated with therapeutic success (0.95 μg/ml and 219.36 [P = 0.0009 and 0.0004, respectively]). The therapeutic success rates among patients infected with susceptible (MIC ≤ 8 μg/ml), susceptible-dose dependent (S-DD) (MIC = 16 or 32 μg/ml), and resistant (MIC ≥ 64 μg/ml) isolates were 67% (14/21), 20% (1/5), and 0% (0/6), respectively. A dose/MIC ratio >50 was associated with a success rate of 74% (14/19), compared to 8% (1/13) for a dose/MIC ratio ≤50 (P = 0.0003). Our data suggest that both fluconazole MIC and dose/MIC ratio correlate with the therapeutic response to fluconazole among patients with candidemia. In clinical practice, dose/MIC ratio might prove easier to interpret than breakpoint MICs, since it quantitates the effects of increasing fluconazole doses that are alluded to in the S-DD designation.

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