The Extent and Impact of Variation in ADME Genes in Sub-Saharan African 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.

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

10.1101/2020.06.14.108217 ◽

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.

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

10.1101/2021.05.16.444330 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22157786 ◽

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.

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A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1413453112 ◽

2015 ◽

Vol 112 (3) ◽

pp. 845-850 ◽

Cited By ~ 86

Author(s):

Annettee Nakimuli ◽

Olympe Chazara ◽

Susan E. Hiby ◽

Lydia Farrell ◽

Stephen Tukwasibwe ◽

...

Keyword(s):

Risk Factor ◽

Maternal Mortality ◽

Odds Ratio ◽

Centromeric Region ◽

Killer Cell ◽

Mulago Hospital ◽

Genetic Studies ◽

African Populations ◽

Sub Saharan ◽

European Populations

In sub-Saharan Africans, maternal mortality is unacceptably high, with >400 deaths per 100,000 births compared with <10 deaths per 100,000 births in Europeans. One-third of the deaths are caused by pre-eclampsia, a syndrome arising from defective placentation. Controlling placentation are maternal natural killer (NK) cells that use killer-cell immunoglobulin-like receptor (KIR) to recognize the fetal HLA-C molecules on invading trophoblast. We analyzed genetic polymorphisms of maternal KIR and fetal HLA-C in 484 normal and 254 pre-eclamptic pregnancies at Mulago Hospital, Kampala, Uganda. The combination of maternal KIR AA genotypes and fetal HLA-C alleles encoding the C2 epitope associates with pre-eclampsia [P = 0.0318, odds ratio (OR) = 1.49]. The KIR genes associated with protection are located in centromeric KIR B regions that are unique to sub-Saharan African populations and contain the KIR2DS5 and KIR2DL1 genes (P = 0.0095, OR = 0.59). By contrast, telomeric KIR B genes protect Europeans against pre-eclampsia. Thus, different KIR B regions protect sub-Saharan Africans and Europeans from pre-eclampsia, whereas in both populations, the KIR AA genotype is a risk factor for the syndrome. These results emphasize the importance of undertaking genetic studies of pregnancy disorders in African populations with the potential to provide biological insights not available from studies restricted to European populations.

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Prevalence of Factor V Leiden Mutation in Non-European Populations

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655963 ◽

1997 ◽

Vol 77 (02) ◽

pp. 329-331 ◽

Cited By ~ 55

Author(s):

Guglielmina Pepe ◽

Olga Rickards ◽

Olga Camacho Vanegas ◽

Tamara Brunelli ◽

Anna Maria Gori ◽

...

Keyword(s):

Factor V Leiden ◽

Indirect Evidence ◽

Factor V ◽

Factor V Leiden Mutation ◽

The World ◽

Fv Leiden ◽

Sub Saharan ◽

Low Prevalence ◽

European Populations ◽

Apparently Healthy

SummaryA difference in the prevalence of venous thromboembolism (TE) in major human groups has been described and an uneven distribution of FV Leiden mutation over the world has recently been reported.We investigated FV Leiden mutation in 584 apparently healthy sub#jects mostly from populations different from those previously investi#gated: 170 Europeans (Spanish, Italians), 101 sub-saharan Africans (Fon, Bariba, Berba, Dendi), 115 Asians (Indonesians, Chinese, Tharus), 57 Amerindians (Cayapa), 84 Afroamericans (Rio Cayapa, Viche), and 57 Ethiopians (Amhara, Oromo).The mutation was detected in only 1/115 Asian (Tharu) and in 5/170 Europeans (4 Italians, 1 Spanish).These data confirm that in non-Europeans the prevalence of FV mutation is at least 7 times lower than in Europeans and provide indirect evidence of a low prevalence not only of the FV Leiden gene but also of other genes leading to more severe thrombophilia. Finally, findings from the literature together with those pertaining to this study clearly show a marked heterogeneity among Europeans.

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