CYP2D6: a global analysis of phenotypic and genotypic variation in search of radical cure of Plasmodium vivax malaria

Thesis (Master's)--University of Washington, 2016-06University Of Washington Abstract CYP2D6: a global analysis of phenotypic and genotypic variation in search of radical cure of Plasmodium vivax malaria Aparna Sen Chair of the Supervisory Committee: Ian Painter, Clinical Assistant Professor Department of Health Background: Malaria is a debilitating, life-threatening disease caused by Plasmodium protozoan parasites. Female Anopheles mosquitoes are the vector for the disease and responsible for disease transmission. In 2013, malaria deaths were estimated to be 584,000, mostly among sub-Saharan African children younger than five years of age. Even though huge number of morbidity and mortality are associated with this disease, malaria is preventable and can be cured. Efforts for increased malaria prevention and radical cure measures are being taken to reduce and eventually eradicate malaria globally. CYP2D6 is an enzyme encoded by the cyp2d6 gene. The gene is located in the q arm of chromosome 22 (22q13.1) and is known to be highly polymorphic. The enzyme is responsible for metabolism of 25% of clinically used drugs. Another enzyme important in malaria treatment is Glucose-6-phosphate dehydrogenase (G6PD) encoded by a highly polymorphic g6pd gene. G6PD deficiency is the most common enzyme deficiency in the world, known to be present in about 400 million people worldwide. This deficiency is found mostly in the malaria endemic regions of the world. Currently, the main treatment for P. vivax malaria is with chloroquine and primaquine drugs. The aim of this research is to study the importance of CYP2D6 variants in the P. vivax endemic regions of the world and to evaluate whether these mutations are linked with primaquine failure. We will also study G6PD deficiencies in those regions of the world. This data would serve as a step towards the ultimate goal for P. vivax malarial treatment, radical cure and elimination. Methods: Data was collected by conducting literature survey and was focused towards geographic distribution of CYP2D6. We searched English-language literature in Pubmed and CYP2D6 databases. Additional information was obtained by searching reference lists of all relevant articles. Search items for CYP2D6 included keyword searches such as geographical distribution, polymorphism, phenotypes, genotypes, malaria, P.vivax malaria, primaquine treatment. A similar literature search was also conducted on G6PD deficiency. A detailed CYP2D6 database and malarial database search was conducted for P. vivax prevalence data in malaria endemic countries. Finally global malaria report was accessed from WHO malaria report 2014. Results: Preliminary results did indicate that there is a link between primaquine drug metabolism and the poor metabolizer and intermediate metabolizer variants of CYP2D6. However, further studies need to be conducted to establish this role. Conclusion: Globally, the poor metabolizer and intermediate metabolizers of CYP2D6 might hinder primaquine metabolism. Furthermore, G6PD deficiency along with the CYP2D6 mutation might be a major problem in P. vivax endemic regions of the world. Rapid point-of care detection tests for these mutations can be developed in the future to prevent relapses from malarial episodes and fatalities from primaquine treatment and seek other effective drugs for radical cure and eradication of malaria