eprintid: 8767 rev_number: 4 userid: 6 dir: disk0/00/00/87/67 datestamp: 2011-11-10 19:55:35 lastmod: 2016-11-15 13:47:38 status_changed: 2011-11-10 19:55:35 type: thesis_degree metadata_visibility: show contact_email: turbogrl@optonline.net item_issues_count: 0 eprint_status: archive creators_name: Remo, Allison M. creators_email: turbogrl@optonline.net title: Hemoglobinopathies in Children within a Malaria Holoendemic Region of Western Kenya ispublished: unpub divisions: sch_gsph_infectiousdiseasesmicrobiology full_text_status: public keywords: Malaria; Sickle Cell Trait 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. date: 2007-09-27 date_type: completed institution: University of Pittsburgh refereed: TRUE etdcommittee_type: committee_chair etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Perkins, Douglas J etdcommittee_name: Martinson, Jeremy etdcommittee_name: Ferrell, Robert etdcommittee_email: djp@pitt.edu etdcommittee_email: jmartins@pitt.edu etdcommittee_email: rferrell@hgen.pitt.edu etdcommittee_id: DJP etdcommittee_id: JMARTINS etdcommittee_id: RFERRELL etd_defense_date: 2007-07-13 etd_approval_date: 2007-09-27 etd_submission_date: 2007-07-31 etd_access_restriction: immediate etd_patent_pending: FALSE assigned_doi: doi:10.5195/pitt.etd.2011.8767 thesis_type: thesis degree: MS committee: Douglas J. Perkins (djp@pitt.edu) - Committee Chair committee: Jeremy Martinson (jmartins@pitt.edu) - Committee Member committee: Robert Ferrell (rferrell@hgen.pitt.edu) - Committee Member etdurn: etd-07312007-160437 other_id: http://etd.library.pitt.edu/ETD/available/etd-07312007-160437/ other_id: etd-07312007-160437 citation: Remo, Allison M. (2007) Hemoglobinopathies in Children within a Malaria Holoendemic Region of Western Kenya. Master's Thesis, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/8767/1/Remothesis.pdf