Pharmacogenomic variation in the Malagasy population: implications for the antimalarial drug primaquine metabolism.

Antimalarial primaquine (PQ) eliminates liver hypnozoites of   gene variation contributes to PQ therapeutic failure. Additional gene variation may contribute to PQ efficacy. Information on pharmacogenomic variation in Madagascar, with malaria and a unique population admixture, is scanty.

gene resequencing in the Malagasy, a population at the crossroads between Asia and Africa: a pilot study.

malaria is endemic in Madagascar, where populations have genetic inheritance from Southeast Asia and East Africa. Primaquine, a drug of choice for vivax malaria, is metabolized principally via CYP2D6. variation was characterized by locus-specific gene sequencing and was compared with TaqMan™ genotype data.

Genetic Variation and Its Implication for Vivax Malaria Treatment in Madagascar.

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.

Chemokine receptor gene polymorphisms and COVID-19: Could knowledge gained from HIV/AIDS be important?

Emerging results indicate that an uncontrolled host immune response, leading to a life-threatening condition called cytokine release syndrome (also termed "cytokine storm"), is the major driver of pathology in severe COVID-19. In this pandemic, considerable effort is being focused on identifying host genomic factors that increase susceptibility or resistance to the complications of COVID-19 and translating these findings to improved patient care. In this regard, the chemokine receptor-ligand nexus has been reported as potentially important in severe COVID-19 disease pathogenesis and its treatment.

New Knowledge About CCR5, HIV Infection, and Disease Progression: Is "Old" Still Valuable?

C-C chemokine receptor (CCR) 5 (CCR5) is the main HIV-1 coreceptor involved in virus entry and cell-to-cell spread during acute and chronic infections: such CCR5 and T cell tropic viruses are adapted to and replicate in CD4 memory T cells. Polymorphisms in regulate CCR5 expression, which, in turn, influences HIV infection acquisition and subsequent disease progression. Among these polymorphisms, a 32-bp deletion in the open reading frame ( Δ32) and a single nucleotide polymorphism (SNP) in the promoter (-2459G/A) are the most well-characterized polymorphisms.

CCR5 Promoter Polymorphism -2459G > A: Forgotten or Ignored?

C-C chemokine receptor 5 () polymorphisms, particularly a 32-base pair deletion (∆32) in the open reading frame and -2459G > A in the promoter, are well known for their associations with HIV-1 infection and/or disease progression in a variety of studies. In this era of an HIV cure, where all the emphasis is on ∆32, it seems that -2459G > A has been forgotten or ignored. There is significant importance in the incorporation of the -2459G > A genotype information into studies evaluating new immunologic and chemotherapeutic strategies, and those designing and implementing better treatment strategies with current antiretroviral therapy, doing so would enable a better understanding of the response to the intervention, due to a mechanistic or constitutive explanation.

Parasitemia and Band Sensitivity of the SD Bioline Malaria Ag P.f/Pan Rapid Diagnostic Test in Madagascar.

Current malaria rapid diagnostic tests (RDTs) contain antibodies against -specific histidine-rich protein 2 (PfHRP2), lactate dehydrogenase (pLDH), and aldolase in various combinations. Low or high parasite densities/target antigen concentrations may influence the accuracy and sensitivity of PfHRP2-detecting RDTs. We analyzed the SD Bioline Malaria Ag P.

Human Genetic Variation and HIV/AIDS in Papua New Guinea: Time to Connect the Dots.

Purpose Of Review: Human genetic polymorphisms known to influence HIV acquisition and disease progression occur in Papua New Guinea (PNG). However, no genetic association study has been reported so far. In this article, we review research findings, with a view to stimulate genotype-to-phenotype research.

Histidine-Rich Protein 2 Gene Variation in a Malaria-Endemic Area of Papua New Guinea.

Histidine-rich protein 2 of (PfHRP2) forms the basis of many current malaria rapid diagnostic tests (RDTs). It is concerning that there are parasites that lack part or all of the gene, and thus do not express the PfHRP2 protein; such parasites are not identifiable by PfHRP2-detecting RDTs. Very limited information is available regarding genetic variation in Papua New Guinea (PNG).

Insights into the Performance of SD Bioline Malaria Ag P.f/Pan Rapid Diagnostic Test and Histidine-Rich Protein 2 Gene Variation in Madagascar.

histidine-rich protein 2 (PfHRP2) forms the basis of many current malaria rapid diagnostic tests (RDTs). However, the parasites lacking part or all of the gene do not express the PfHRP2 protein and are, therefore, not identifiable by PfHRP2-detecting RDTs. We evaluated the performance of the SD Bioline Malaria Ag P.

Ensemble survival tree models to reveal pairwise interactions of variables with time-to-events outcomes in low-dimensional setting.

Unraveling interactions among variables such as genetic, clinical, demographic and environmental factors is essential to understand the development of common and complex diseases. To increase the power to detect such variables interactions associated with clinical time-to-events outcomes, we borrowed established concepts from random survival forest (RSF) models. We introduce a novel RSF-based pairwise interaction estimator and derive a randomization method with bootstrap confidence intervals for inferring interaction significance.

Long-term in vitro culture of Plasmodium vivax isolates from Madagascar maintained in Saimiri boliviensis blood.

Background: Plasmodium vivax is the most prevalent human malaria parasite and is likely to increase proportionally as malaria control efforts more rapidly impact the prevalence of Plasmodium falciparum. Despite the prominence of P. vivax as a major human pathogen, vivax malaria qualifies as a neglected and under-studied tropical disease.

A preliminary assessment of and gene polymorphisms in Papua New Guinea - what does it mean for HIV/AIDS?

Polymorphisms in Toll-like receptor () and human β-defensin (hBD, encoded by ) genes have been evaluated for their associations with HIV infection and disease outcomes. Those studies, conducted in various populations under a variety of study designs, generally revealed that specific single nucleotide polymorphisms (SNPs) in , 8, and genes, and copy number variation (CNV) in (encoding hBD-2), (encoding hBD-3), and (encoding hBD-4) genes are among potential genetic factors that can affect susceptibility to HIV infection and/or disease progression. The information regarding their prevalence in Papua New Guinea (PNG) is very limited for SNPs, and not available for CNV.

Associations of Toll-Like Receptor and β-Defensin Polymorphisms with Measures of Periodontal Disease (PD) in HIV+ North American Adults: An Exploratory Study.

Polymorphisms in toll-like receptor (TLR) and β-defensin (DEFB) genes have been recognized as potential genetic factors that can influence susceptibility to and severity of periodontal diseases (PD). However, data regarding associations between these polymorphisms and PD are still scarce in North American populations, and are not available in HIV+ North American populations. In this exploratory study, we analyzed samples from HIV+ adults (n = 115), who received primary HIV care at 3 local outpatient HIV clinics and were monitored for PD status.

Defensin gene variation and HIV/AIDS: a comprehensive perspective needed.

Both α- and β-defensins have anti-human immunodeficiency virus activity. These defensins achieve human immunodeficiency virus inhibition through a variety of mechanisms, including direct binding with virions, binding to and modulation of host cell-surface receptors with disruption of intracellular signaling, and functioning as chemokines or cytokines to augment and alter adaptive immune responses. Polymorphisms in the defensin genes have been associated with susceptibility to human immunodeficiency virus infection and disease progression.

CCR2, CCR5, and CXCL12 variation and HIV/AIDS in Papua New Guinea.

Polymorphisms in chemokine receptors, serving as HIV co-receptors, and their ligands are among the well-known host genetic factors associated with susceptibility to HIV infection and/or disease progression. Papua New Guinea (PNG) has one of the highest adult HIV prevalences in the Asia-Pacific region. However, information regarding the distribution of polymorphisms in chemokine receptor (CCR5, CCR2) and chemokine (CXCL12) genes in PNG is very limited.

Association of Toll-like receptor polymorphisms with HIV status in North Americans.

Single-nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes TLR2-4 and TLR7-9, but not in TLR1 and TLR6, have been previously evaluated regarding human immunodeficiency virus (HIV) acquisition and disease progression in various populations, most of which were European. In this study, we examined associations between a total of 41 SNPs in 8 TLR genes (TLR1-4, TLR6-9) and HIV status in North American subjects (total n=276 (Caucasian, n=102; African American, n=150; other, n=24)). Stratification of the data by self-identified race revealed that a total of nine SNPs in TLR1, TLR4, TLR6 and TLR8 in Caucasians, and two other SNPs, one each in TLR4 and TLR8, in African Americans were significantly associated with HIV status at P<0.

African ancestry influences CCR5 -2459G>A genotype-associated virologic success of highly active antiretroviral therapy.

Introduction: In a North American, HIV-positive, highly active antiretroviral therapy (HAART)-treated, adherent cohort of self-identified white and black patients, we previously observed that chemokine (C-C motif) receptor 5 (CCR5) -2459G>A genotype had a strong association with time to achieve virologic success (TVLS) in black but not in white patients.

Methods: Using 128 genome-wide ancestry informative markers, we performed a quantitative assessment of ancestry in these patients (n = 310) to determine (1) whether CCR5 -2459G>A genotype is still associated with TVLS of HAART when ancestry, not self-identified race, is considered and (2) whether this association is influenced by varying African ancestry.

Results: We found that the interaction between CCR5 -2459G>A genotype and African ancestry (≤ 0.

Variation in human β-defensin genes: new insights from a multi-population study.

Human β-defensin 2 (hBD-2) and hBD-3, encoded by DEFB4 and DEFB103A, respectively, have shown anti-HIV activity, and both genes exhibit copy number variation (CNV). Although the role of hBD-1, encoded by DEFB1, in HIV-1 infection is less clear, single nucleotide polymorphisms (SNPs) in DEFB1 may influence viral loads and disease progression. We examined the distribution of DEFB1 SNPs and DEFB4/103A CNV, and the relationship between DEFB1 SNPs and DEFB4/103A CNV using samples from two HIV/AIDS cohorts from the United States (n = 150) and five diverse populations from the Coriell Cell Repositories (n = 46).

Worldwide variation in human drug-metabolism enzyme genes CYP2B6 and UGT2B7: implications for HIV/AIDS treatment.

Aim: Hepatic enzymes, CYP2B6 and UGT2B7 play a major role in the metabolism of the widely used antiretroviral drugs efavirenz, nevirapine and zidovudine. In the present study, we provide a view of UGT2B7 haplotype structure, and quantify the genetic diversity and differentiation at both CYP2B6 and UGT2B7 genes on a worldwide scale.

Materials & Methods: We genotyped one intronic and three promoter SNPs, and together with three nonsynonymous SNPs, inferred UGT2B7 alleles in north American (n = 326), west African (n = 133) and Papua New Guinean (n = 142) populations.

Copy Number Variation within Human β-Defensin Gene Cluster Influences Progression to AIDS in the Multicenter AIDS Cohort Study.

Study Background: encoding β-defensin 2 and 3, respectively, inhibit CXCR4-tropic (X4) viruses in vitro. We determined whether Copy Number Variation (CNV) influences time-to-X4 and time-to-AIDS outcomes.

Methods: We utilized samples from a previously published Multicenter AIDS Cohort Study (MACS), which provides longitudinal account of viral tropism in relation to the full spectrum of rates of disease progression.

Chemokine (C-C motif) receptor 5 -2459 genotype in patients receiving highly active antiretroviral therapy: race-specific influence on virologic success.

Background: In patients receiving highly active antiretroviral therapy (HAART), antiretroviral drug-metabolizing enzyme and transporter gene polymorphisms, as well as chemokine receptor gene polymorphisms, may influence response to treatment.

Methods: In a North American, treated, adherent human immunodeficiency virus (HIV)-positive cohort (self-identified whites, n = 175; blacks, n = 218), we investigated whether CYP2B6 (516G>T, 983T>C), UGT2B7 (IVS1+985A>G, 802C>T), MDR1 3435C>T, chemokine (C-C motif) receptor 2 (CCR2) 190G>A, and CCR5 (-2459G>A, Δ32) polymorphisms influenced the time to achieve virologic success (TVLS).

Results: No difference in TVLS was observed between races.

Expanding the Antimalarial Drug Arsenal-Now, But How?

The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins.

Molecular-based assay for simultaneous detection of four Plasmodium spp. and Wuchereria bancrofti infections.

Four major malaria-causing Plasmodium spp. and lymphatic filariasis-causing Wuchereria bancrofti are co-endemic in many tropical and sub-tropical regions. Among molecular diagnostic assays, multiplex polymerase chain reaction (PCR)-based assays for the simultaneous detection of DNAs from these parasite species are currently available only for P.

Treatment with coartem (artemether-lumefantrine) in Papua New Guinea.

A recent drug efficacy trial reported Coartem (artemether-lumefantrine) to be highly effective against Plasmodium falciparum in children less than 5 years of age in Papua New Guinea (PNG). In contrast, we have observed high levels of treatment failures in non-trial conditions in a longitudinal cohort study in the same age group in PNG. Recrudescences were confirmed by genotyping of three different marker genes to provide optimal discrimination power between parasite clones.