Dagne 1 Beza A Dagne Genomics and Medecine Dr Douglas Brutlag March 8 2011 Genetic Variations and Sensitivity to Malaria Malaria is one of the oldest infectious diseases known to man It is caused by the parasitic species Plasmodium Fujioka 2002 Although Plasmodium falciparum is the most common species of this parasitic family that infects the human population the three other known species include Plasmodium ovale Plasmodium vivax and Plasmodium malariae Fujioka 2002 It is transmitted to humans by the bite of female mosquitos acting as the vectors for these parasites Each year there are close to 250 million who suffer from this disease leading to a fatality level that is staggering more than 1 million people WHO 2011 Although the disease is practically eradicated in nations like the U S it remains prevalent in most developing countries The repercussions of this disease include the negative impact it has on the economic expansion of these nations According to the World Health Organization as a result of malaria the annual economic development declines by 1 3 in countries where the disease is most prevalent WHO 2011 Thus it is a relevant problem that this world continues to tackle and researchers are using genomics to better understand the disease and to develop a long term fix through vaccines One of the ways that researchers are exploring such options is by analyzing the various malaria related genetic polymorphisms present in the human population Sensitivity to malaria has evolved throughout human evolution and genetic resistance to malaria is one of most sustained genetic variation preserved through natural selection Dornamraju Krishna Arese Haldane 2006 These mechanisms of resistance are highly Dagne 2 selected for despite some of these variations leading to fetal diseases like those who are homozygotes for sickle cell anemia HbS Interestingly genetic variations resulting in resistance to this disease are constantly changing and various mechanisms of genetic resistance have been adopted by different population groups of the world Some of these mechanisms of genetic resistance developed as early as 10 000 years ago Abdalla Saad Pasavola 2004 Different forms of evolutionary selection for malaria resistance developed include mutation in genes coding for hemoglobin membrane proteins of red blood cells as well as those of liver cells One of the most common forms of selectivity to malaria are ones that influence the response of red blood cells to the invasion of a Plasmodium parasite Pathology of Malaria in the Human Body After the mosquito bites the human skin the parasites sporozoites present in the mosquito s saliva will enter the blood stream of the individual Hisashi 2002 Once inside the body they attack the liver cells and the sporozoites will mature releasing merozoites which will go to infect blood cells And these merozoites continue to divide inside the blood cells and these parasites will go and attack other erythrocytes The human immune system has difficulty implementing an effective defense against this attack because these merozoites have developed savvy techniques to bypass the body s immune response Obviously a major problem the immune systems faces is that T cells cannot attack the red blood cells because erythrocytes lack MHC proteins Hisashi 2002 And while it is developing in the liver cells the parasites remain concealed from the immune system and one possible way that the body s defense system can rid the body of these parasites would be by employing the aid of the spleen However these parasites have developed a way to avoid circulating in the blood stream and thus never reaching the spleen Once these parasites are inside the red blood cells they produce a series of proteins Dagne 3 that are sent to the surface of the cell Hasashi 2002 These membrane bound proteins bind to adhesive molecules on the endothelial surface of blood vessels Abdalla Saad Pasvol 2004 Thus when the adoptive immune system cannot tackle the complexities of these parasitic invasions genetic variations selected for by nature result in decreased sensitivity to the disease Mendelian Genetic Disorders and Resistance Some of the most common mendelian genetic disorders have shown a correlation with a resistance to malaria Some of these disorders include afflictions brought on by a mutant of the HBB gene HbS HbC and HbE Kwiatkowski 2005 HbS and HbC is a variant that is most commonly associated with Africans African decedents as well as individuals from the middle east However HbE is one variation that is common at high frequencies in population of Southeastern Asia Another variant that results in hemolytic anemia but leads to malaria resistance is variations found in the G6PD gene Tishkoff 2001 This gene codes for an enzyme that produces a reducing agent that helps the red blood cells cope with an oxidative stress caused by Plasmodium parasites Tishkoff 2001 This stress is present as iron is produced when the parasites degrade hemoglobin There are many more genetic variations such as those listed below which exhibit at high frequency within a few specific populations giving them a genetic advantage over others who do not have such traits see Figure 1 There is little known about the molecular basis behind how these variations lead to resistance to malaria while others are well understood and potential therapeutic treatments are being developed as a result Dagne 4 genetic gene has been one vaccines developing scientists helping adaptation that is in their hopes for Kwiatkowski Dominic How Malaria Has Affected the Human Genome and What Human Genetics Can Teach Us about Malaria Genet 77 2005 171 90 Print the FY Variation in Dagne 5 for malaria Dornamraju Krishna Arese Haldane 2006 This gene codes for the Duffy antigen that is associated with the surface of red blood cells This antigen is not expressed in some regions of Africa and it is a genetic variation that results in a resistance to the parasitic variant P Vivax This genetic variation led researchers to find a parasitic derived protein that binds to this Duffy antibody Kwiatkowski 2005 With this knowledge current research is looking into developing vaccines that will manipulate the parasites s ability to bind to the body s Duffy receptor Another variation leading to decreased sensitivity to malaria is the gene HLA B Dornamraju Krishna Arese Haldane 2006 This gene codes for an antigen presenting protein MHC like protein and a variant of this gene
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