scholarly journals CYP2D6 Genetic Variation and Its Implication for Vivax Malaria Treatment in Madagascar

2021 ◽  
Vol 12 ◽  
Author(s):  
Rajeev K. Mehlotra ◽  
Andrea Gaedigk ◽  
Rosalind E. Howes ◽  
Tovonahary A. Rakotomanga ◽  
Arsene C. Ratsimbasoa ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Vivax Malaria ◽  
Severe Disease ◽  
Therapeutic Failure ◽  
Cyp2d6 Activity ◽  
Human Malaria Parasite ◽  
Frequency Distributions ◽  
African Populations ◽  
Blood Stage Infection ◽  
Health Districts

Plasmodium vivax is one of the five human malaria parasite species, which has a wide geographical distribution and can cause severe disease and fatal outcomes. It has the ability to relapse from dormant liver stages (hypnozoites), weeks to months after clearance of the acute blood-stage infection. An 8-aminoquinoline drug primaquine (PQ) can clear the hypnozoites, and thus can be used as an anti-relapse therapeutic agent. Recently, a number of studies have found that its efficacy is compromised by polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene; decreased or absence of CYP2D6 activity contributes to PQ therapeutic failure. The present study sought to characterize CYP2D6 genetic variation in Madagascar, where populations originated from admixture between Asian and African populations, vivax malaria is endemic, and PQ can be deployed soon to achieve national malaria elimination. In a total of 211 samples collected from two health districts, CYP2D6 decreased function alleles CYP2D6*10, *17, *29, *36+*10, and *41 were observed at frequencies of 3.55–17.06%. In addition, nonfunctional alleles were observed, the most common of which were CYP2D6*4 (2.13%), *5 (1.66%), and the *4x2 gene duplication (1.42%). Given these frequencies, 34.6% of the individuals were predicted to be intermediate metabolizers (IM) with an enzyme activity score (AS) ≤ 1.0; both the IM phenotype and AS ≤ 1.0 have been found to be associated with PQ therapeutic failure. Furthermore, the allele and genotype frequency distributions add to the archaeological and genomic evidence of Malagasy populations constituting a unique, Asian-African admixed origin. The results from this exploratory study provide fresh insights about genomic characteristics that could affect the metabolism of PQ into its active state, and may enable optimization of PQ treatment across human genetic diversity, which is critical for achieving P. vivax elimination.

scholarly journals Constellation: a tool for rapid, automated phenotype assignment of a highly polymorphic pharmacogene, CYP2D6, from whole-genome sequences

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Greyson P Twist ◽  
Andrea Gaedigk ◽  
Neil A Miller ◽  
Emily G Farrow ◽  
Laurel K Willig ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Reference Method ◽  
Whole Genome ◽  
Automated Identification ◽  
Structural Variations ◽  
Functional Variation ◽  
Cyp2d6 Activity ◽  
Drug Choice ◽  
Extreme Phenotypes ◽  
Number Variation

Abstract An important component of precision medicine—the use of whole-genome sequencing (WGS) to guide lifelong healthcare—is electronic decision support to inform drug choice and dosing. To achieve this, automated identification of genetic variation in genes involved in drug absorption, distribution, metabolism, excretion and response (ADMER) is required. CYP2D6 is a major enzyme for drug bioactivation and elimination. CYP2D6 activity is predominantly governed by genetic variation; however, it is technically arduous to haplotype. Not only is the nucleotide sequence of CYP2D6 highly polymorphic, but the locus also features diverse structural variations, including gene deletion, duplication, multiplication events and rearrangements with the nonfunctional, neighbouring CYP2D7 and CYP2D8 genes. We developed Constellation, a probabilistic scoring system, enabling automated ascertainment of CYP2D6 activity scores from 2×100 paired-end WGS. The consensus reference method included TaqMan genotyping assays, quantitative copy-number variation determination and Sanger sequencing. When compared with the consensus reference Constellation had an analytic sensitivity of 97% (59 of 61 diplotypes) and analytic specificity of 95% (116 of 122 haplotypes). All extreme phenotypes, i.e., poor and ultrarapid metabolisers were accurately identified by Constellation. Constellation is anticipated to be extensible to functional variation in all ADMER genes, and to be performed at marginal incremental financial and computational costs in the setting of diagnostic WGS.

scholarly journals How Does Mother-to-Child Transmission of HIV Differ Among African Populations? Lessons from MBL2 Genetic Variation in Zimbabweans

2014 ◽  
Vol 18 (7) ◽  
pp. 454-460 ◽  
Author(s):  
Kudakwashe Mhandire ◽  
Gavin Pharo ◽  
Gwendolene Q. Kandawasvika ◽  
Kerina Duri ◽  
Marelize Swart ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Mother To Child Transmission ◽  
Child Transmission ◽  
African Populations ◽  
Mother To Child

scholarly journals Evidence and Implications of Mortality Associated with Acute Plasmodium vivax Malaria

2013 ◽  
Vol 26 (1) ◽  
pp. 36-57 ◽  
Author(s):  
J. Kevin Baird
Keyword(s):  
Vivax Malaria ◽  
Clinical Evidence ◽  
Severe Disease ◽  
Single Species ◽  
Complex Problem ◽  
Low Grade ◽  
Systematic Analysis ◽  
Significant Burden ◽  
Plasmodium Vivax Malaria ◽  
Significant Mortality

SUMMARYVivax malaria threatens patients despite relatively low-grade parasitemias in peripheral blood. The tenet of death as a rare outcome, derived from antiquated and flawed clinical classifications, disregarded key clinical evidence, including (i) high rates of mortality in neurosyphilis patients treated with vivax malaria; (ii) significant mortality from zones of endemicity; and (iii) the physiological threat inherent in repeated, very severe paroxysms in any patient, healthy or otherwise. The very well-documented course of this infection, with the exception of parasitemia, carries all of the attributes of “perniciousness” historically linked to falciparum malaria, including severe disease and fatal outcomes. A systematic analysis of the parasite biomass in severely ill patients that includes blood, marrow, and spleen may ultimately explain this historic misunderstanding. Regardless of how this parasite is pernicious, recent data demonstrate that the infection comes with a significant burden of morbidity and associated mortality. The extraordinary burden of malaria is not heavily weighted upon any single continent by a single species of parasite—it is a complex problem for the entire endemic world, and both species are of fundamental importance. Humanity must rally substantial resources, intellect, and energy to counter this daunting but profound threat.

UDP-glucuronosyltransferase genetic variation in North African populations: a comparison with African and European data

2018 ◽  
Vol 45 (6-8) ◽  
pp. 516-523 ◽  
Author(s):  
Apolonia Novillo ◽  
María Gaibar ◽  
Alicia Romero-Lorca ◽  
Hassen Chaabani ◽  
Nadir Amir ◽  
...  
Keyword(s):  
Genetic Variation ◽  
North African ◽  
European Data ◽  
African Populations ◽  
Udp Glucuronosyltransferase

scholarly journals Phylogeography of Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) (Diptera: Culicidae) based on mitochondrial DNA variations

2005 ◽  
Vol 86 (1) ◽  
pp. 1-11 ◽  
Author(s):  
LAURENCE MOUSSON ◽  
CATHERINE DAUGA ◽  
THOMAS GARRIGUES ◽  
FRANCIS SCHAFFNER ◽  
MARIE VAZEILLE ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Genetic Variation ◽  
East Asia ◽  
Ivory Coast ◽  
Nadh Dehydrogenase ◽  
South East Asia ◽  
Nadh Dehydrogenase Subunit ◽  
African Populations ◽  
The Tropics ◽  
Dna Variations

Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) are the most important vectors of the dengue and yellow-fever viruses. Both took advantage of trade developments to spread throughout the tropics from their native area: A. aegypti originated from Africa and A. albopictus from South-East Asia. We investigated the relationships between A. aegypti and A. albopictus mosquitoes based on three mitochondrial-DNA genes (cytochrome b, cytochrome oxidase I and NADH dehydrogenase subunit 5). Little genetic variation was observed for A. albopictus, probably owing to the recent spreading of the species via human activities. For A. aegypti, most populations from South America were found to be genetically similar to populations from South-East Asia (Thailand and Vietnam), except for one sample from Boa Vista (northern Amazonia), which was more closely related to samples from Africa (Guinea and Ivory Coast). This suggests that African populations of A. aegypti introduced during the slave trade have persisted in Boa Vista, resisting eradication campaigns.

scholarly journals Thrombocytopenia inPlasmodium vivaxMalaria: How Significant?

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Arti Muley ◽  
Jitendra Lakhani ◽  
Saurabh Bhirud ◽  
Abhinam Patel
Keyword(s):  
Platelet Count ◽  
Serum Creatinine ◽  
Vivax Malaria ◽  
Severe Disease ◽  
Lung Involvement ◽  
Ventilator Support ◽  
Altered Sensorium ◽  
Normal Platelet Count ◽  
Normal Platelet ◽  
Hematological Profile

Introduction. Thrombocytopenia is frequently noticed withP. falciparummalaria but is less reported and studied withP. vivax.Materials and Methods. The study was conducted in the Department of Medicine, SBKS MI & RC, Pipariya. We included patients who were diagnosed with vivax malaria. The data regarding their clinical and hematological profile was collected and analysed.Result. A total of 66 patients were included. 42 (63%) had platelet count <100000/mm3. Mean platelet count was 1,18,650, range being 8000/mm3–6,10,000/mm3. Amongst those with thrombocytopenia, 16 (38.09%) had anemia, 14 (33.33%) had serum creatinine >1.2 gm/dL, 15 (35.71%) had jaundice (s. bilirubin > 1.2), 2 (4.76%) had altered sensorium, 6 (14.28%) had ARDS, 2 needed ventilator support, and 1 expired. Amongst those with normal platelet count, 5 (20.83%) had anemia and 1 had jaundice whereas none had elevated s. creatinine, altered sensorium, or lung involvement.Conclusion. Thrombocytopenia is now being seen more commonly with vivax malaria. Patients with platelet count <1 lac/cumm have more severe disease.

scholarly journals Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa

2021 ◽  
Author(s):  
Elizabeth G. Atkinson ◽  
Shareefa Dalvie ◽  
Yakov Pichkar ◽  
Allan Kalungi ◽  
Lerato Majara ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Genetic Variation ◽  
Variant Interpretation ◽  
African Continent ◽  
Transmission Rates ◽  
Genetics Research ◽  
African Populations ◽  
The World ◽  
Eastern And Southern Africa ◽  
Language Transmission

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We further find significantly higher language transmission rates for matrilineal groups as compared to patrilineal. We highlight both the diversity of variation within the African continent, as well as how within-Africa variation can be informative for broader variant interpretation; many variants appearing rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity within Africa.

scholarly journals Pharmacokinetics/pharmacodynamics of chloroquine and artemisinin-based combination therapy with primaquine

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
André Daher ◽  
Ghait Aljayyoussi ◽  
Dhelio Pereira ◽  
Marcus V. G. Lacerda ◽  
Márcia A. A. Alexandre ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Half Life ◽  
Vivax Malaria ◽  
Drug Exposure ◽  
Area Under The Curve ◽  
Compartmental Analysis ◽  
Normal Activity ◽  
Radical Cure ◽  
Cyp2d6 Activity ◽  
Long Acting

Abstract Background Activation of hypnozoites of vivax malaria causes multiple clinical relapses, which contribute to the Plasmodium vivax burden and continuing transmission. Artemisinin-based combination therapy (ACT) is effective against blood-stage P. vivax but requires co-administration with primaquine to achieve radical cure. The therapeutic efficacy of primaquine depends on the generation of a therapeutically active metabolite via cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 metabolism has been associated with primaquine treatment failure. This study investigated the association between impaired CYP2D6 genotypes, drug-exposure to the long-acting ACT component (schizonticidal drugs) and tolerance and efficacy. Methods Adult patients with acute vivax malaria were enrolled in a recently completed trial and treated with artesunate–mefloquine, chloroquine or artemether–lumefantrine. All received concomitant primaquine (0.5 mg/kg/day for 7–9 days). The association between efficacy and safety and drug exposure was explored using area-under-the-curve (AUC) and half-life (t1/2) estimates obtained by non-compartmental analysis of the long half-life drugs. Parasite recurrences by day 63 were categorized as related relapses or re-infections/unrelated hypnozoite activation by genotyping three microsatellite loci and two polymorphic loci of merozoite surface antigen-1. The CYP2D6 genotype was identified with Taqman assays by real-time PCR to 9 polymorphisms (8 SNPs and one deletion). Impaired CYP2D6 activity was inferred using the Activity Score System. Results Most recurrences in the ASMQ (67%), CQ (80%) and AL (85%) groups were considered related relapses. Eight of nine (88.9%) of the patients with impaired CYP2D6 activity relapsed with related parasite compared to 18/25 (72%) with normal activity (RR = 1.23, 0.88; 1.72, p = 0.40). There were no associations between the measured PK parameters and recurrence. Patients with longer chloroquine half-lives had more pruritus (RR = 1.09, 1.03; 1.14, p = 0.001). Higher CQ AUCs were associated with reduced falls in haemoglobin by day 14 (Coef − 0.02, − 0.005; − 0.03, p = 0.01). All regimens were well tolerated. Conclusion Genotyping of P. vivax showed that activation of related (homologous) hypnozoites was the most frequent cause of recurrence. The high proportion of the impaired CYP2D6 activity among patients with recurrent infections suggests that slow primaquine metabolism might influence related relapse rates in Brazil among patients receiving primaquine for radical cure, although confirmatory studies are needed. There was no association between drug exposure of the long-acting ACT component (schizonticidal drugs) and risk of related relapse. ACT was well tolerated. These results provide further re-assurance about the safety and efficacy of ACT when combined with short course primaquine to treat uncomplicated malaria vivax in Brazil. Trial registration RBR-79s56s (http://www.ensaiosclinicos.gov.br/rg/RBR-79s56s/)

Evolved to vary: genome and epigenome variation in the human pathogen Helicobacter pylori

2020 ◽  
Author(s):  
Florent Ailloud ◽  
Iratxe Estibariz ◽  
Sebastian Suerbaum
Keyword(s):  
Helicobacter Pylori ◽  
Genetic Variation ◽  
Fitness Landscape ◽  
Severe Disease ◽  
Asymptomatic Infection ◽  
Peptic Ulcers ◽  
Human Pathogens ◽  
Technological Advances ◽  
H Pylori ◽  
Fast Adaptation

ABSTRACT Helicobacter pylori is a Gram-negative, spiral shaped bacterium that selectively and chronically infects the gastric mucosa of humans. The clinical course of this infection can range from lifelong asymptomatic infection to severe disease, including peptic ulcers or gastric cancer. The high mutation rate and natural competence typical of this species are responsible for massive inter-strain genetic variation exceeding that observed in all other bacterial human pathogens. The adaptive value of such a plastic genome is thought to derive from a rapid exploration of the fitness landscape resulting in fast adaptation to the changing conditions of the gastric environment. Nevertheless, diversity is also lost through recurrent bottlenecks and H. pylori’s lifestyle is thus a perpetual race to maintain an appropriate pool of standing genetic variation able to withstand selection events. Another aspect of H. pylori’s diversity is a large and variable repertoire of restriction-modification systems. While not yet completely understood, methylome evolution could generate enough transcriptomic variation to provide another intricate layer of adaptive potential. This review provides an up to date synopsis of this rapidly emerging area of H. pylori research that has been enabled by the ever-increasing throughput of Omics technologies and a multitude of other technological advances.

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