The occurence, distribution and frequency of membrane transporter resistance alleles in <i>Plasmodium falciparum</i> and their association with response and resistance to Arteminisin based combination therapy (ART) in Northern Nigeria

Malaria infection is caused by, <i>Plasmodium falciparum</i> (<i>P. falciparum</i>) parasite. It is the most significant cause of high morbidity and mortality rate in humans. This has created an enormous social and economic burden in many endemic regions in the world. Disturbingly, <i>P. falciparum</i> genome has shown to have recently developed resistance to the most successful related group of drug treatment, known as Artemisinin combination therapies (ACTs), primarily in parts of South East Asia, but possibly also in other parts of the world e.g. East Africa.<br/>The purpose of this research was to; analyse the occurrence and distribution frequency of membrane transporter resistance alleles, in two different <i>P. falciparum</i> proteins, that possibly confer resistance to Artemisinin, and statistically analyse whether any of these resistance alleles; show a significant association with the response, and resistance of ACT’s, present in Northern Nigeria. The two membrane transporter proteins, studied in this project were, firstly, the <i>P. falciparum</i> chloroquine resistance transporter (<i>Pfcrt</i>), which belongs to the drug metabolite transporters; that acts by directly facilitating the efflux of chloroquine, from the digestive vacuole. The second protein associated with the multi-drug resistance, in <i>P. falciparum</i>, is the <i>Pfmdr</i>1 gene, which belongs to the ATP binding cassette (ABC) superfamily of transporters. The common polymorphism in the <i>Pfcrt</i> protein, is an A or C allele at position 228 in the coding sequence; which causes a Lysine residue to be changed to a Threonine residue (c.228A&gt;C p. K76T). The <i>Pfmdr</i>1 gene, has two common resistance alleles, associated with drug resistance, namely c.258A&gt;C (p. N86Y) and c.452A&gt;C (p.N184Y). These changes in amino acids, in both of the proteins confer resistance to specific drug treatment.<br/>Six-hundred individuals, suffering from uncomplicated malaria symptoms, who were also receiving the ACT ‘Artemether-Lumefantrine (Coartem) treatment, were chosen for this research. The statistical result showed that, 209 samples had the malaria infection, which includes 169 with the resistance alleles. The polymorphic alleles included; 75 samples with the <i>Pfcrt</i> resistance alleles, 71 samples had the <i>Pfmdr1-184</i>Y variant and 66 samples had the <i>Pfmdr1-86</i>Y variant. Randomly, selected malaria infected sample results showed that, 19 did not respond to treatment whereas 45 responded. There were 12 unresponsive and 21 responsive samples, with the <i>Pfcrt</i> resistance alleles. The combined <i>Pfmdr1</i> resistance alleles results showed that, among the unresponsive samples, 5 samples had both the <i>Pfmdr1</i> variant alleles, 8 samples had either one of the variants and 2 samples had neither. The responsive group showed that, six samples had both the <i>Pfmdr1 </i>variants, 29 samples had either one of the <i>Pfmdr1</i> variant and 10 samples had neither. The combined resistance alleles showed that, within the unresponsive groups, 5 samples had the combined resistance alleles and 14 samples had either the <i>Pfmdr1</i> or the <i>Pfcrt</i> resistance alleles. The responsive groups showed that, only one sample had both resistance genes, 38 samples had either <i>Pfmdr1</i> or Pfcrt and 6 samples had neither resistance allele. These results significantly showed that, an individual with malaria infection would have either one or more of the malaria resistance alleles, used in this study. Significantly, the results of this study also showed that one of the analysed polymorphism is probably not enough to provide resistance to ACTs, but it is enough for chloroquine resistance. These significant results could perhaps be used as a baseline, for future larger West African population study, which should positively confirm the findings in this research.

Name dc:type.qualificationname

Masters by Research

Level dc:type.qualificationlevel

Masters Thesis

Grantor dc:publisher.institution

Abertay University

Year dc:date.issued

2017

Author dc:creator

• Hanson-Nortey, Maxine

Advisors dc:contributor.advisor

• Walker, Graeme
• Deeni, Yusuf

• Resistance alleles
• Plasmoduim falciparum
• Artemisinin ased combination therapy

Language dc:language

eng

Identifier

oai:rke.abertay.ac.uk:studenttheses/a430a48e-b504-496d-83ec-2f62c2b65309

OAI identifier oai:identifier

oai:rke.abertay.ac.uk:studenttheses/a430a48e-b504-496d-83ec-2f62c2b65309