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Hemoglobinopathies in Children within a Malaria Holoendemic Region of Western Kenya

Remo, Allison M. (2007) Hemoglobinopathies in Children within a Malaria Holoendemic Region of Western Kenya. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Plasmodium falciparum malaria is one of the predominant causes of morbidity and mortality in children under five years of age in sub-Saharan Africa. In malaria endemic regions, the intensity of transmission and the age at which malaria is first acquired are important in conditioning disease outcomes. In addition, inter-individual variability in disease severity among age-matched children (aged <3 yrs) with similar levels of parasite exposure is largely determined by genetic variability. Historical exposure to malaria in endemic populations has exerted tremendous selective pressure on the human genome, particularly in the host-immune response genes that mediate susceptibility and clinical outcomes. Hemoglobinopathies, such as the alpha thalassemia 3.7 kb deletion and sickle-cell trait (HbAS) also confer protection against severe malaria through a mechanism(s) that are yet to be fully elucidated. As such, this study examined the role of alpha thalassemia 3.7 kb deletion and HbAS in protection against severe malaria anemia (SMA) in children (n=468; aged 3-36 months) residing in a holoendemic P. falciparum transmission region of western Kenya. These investigations demonstrated that successful genotyping of the deletion required high-quality genomic DNA from large volumes of whole blood that was unavailable for most of the small, underweight-for-age, severely anemic children in which DNA was isolated from dried blood spots. Results presented here further demonstrated that the HbAS genotype was significantly associated with a reduced burden of both low (<10%; P=0.03) and high (greater than or equal to 10%; P<0.001) pigment-containing monocytes (PCM). In addition, hemoglobin (Hb; P=0.05) and red blood cell (RBC; P=0.04) counts were significantly higher in the HbAS group relative to children with the HbAA genotype. The HbAS genotype was also significantly associated with protection against SMA using both the World Health Organization (i.e., <5.0 g/dL; P=0.04) and modified definitions of SMA (i.e., <6.0 g/dL; P=0.02). Taken together, results presented here suggest that the HbAS genotype confers protection against SMA by reducing the natural acquisition of malarial pigment (hemozoin) in monocytes. This study has significant public health importance by demonstrating that one of the mechanisms by which HbAS provides protection against SMA is through reducing the overall burden of hemozoin in monocytes.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Remo, Allison M.turbogrl@optonline.net
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPerkins, Douglas Jdjp@pitt.eduDJP
Committee MemberMartinson, Jeremyjmartins@pitt.eduJMARTINS
Committee MemberFerrell, Robertrferrell@hgen.pitt.eduRFERRELL
Date: 27 September 2007
Date Type: Completion
Defense Date: 13 July 2007
Approval Date: 27 September 2007
Submission Date: 31 July 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Malaria; Sickle Cell Trait
Other ID: http://etd.library.pitt.edu/ETD/available/etd-07312007-160437/, etd-07312007-160437
Date Deposited: 10 Nov 2011 19:55
Last Modified: 15 Nov 2016 13:47
URI: http://d-scholarship.pitt.edu/id/eprint/8767

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