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Item HOST CYTOKINE GENE POLYMORPHISMS AND PARASITE GENETIC VARIABILITY IN DETERMINING THE DISEASE OUTCOME OF Plasmodium falciparum INFECTION(2012-09) OYEDEJI, S.IMalaria, the world’s most important tropical parasitic disease is caused by Plasmodium species. Infection with Plasmodium falciparum can result in one of three possible disease outcomes: Asymptomatic (AS), Uncomplicated Malaria (UM) or Severe Malaria (SM). Information on host genetic factors and parasite genetic diversity can improve understanding of the disease pathogenesis. In this study, the genetic diversity of P. falciparum isolates as well as polymorphisms in host cytokine genes was investigated in relation to the outcome of P. falciparum infection. Four hundred and thirty-seven children recruited from the Specialist Hospital, Lafia, Nasarawa State were assigned into UM or SM based on malaria severity, determined by clinical and laboratory diagnoses. Asymptomatic children recruited from primary schools within the study location constituted the control group (AS). Plasmodium falciparum infection was confirmed by PCR-based assay of SSUrRNA genes. Genetic diversity of P. falciparum was analyzed by genotyping the polymorphic domains of the Merozoite Surface Protein 2 (MSP-2). Host cytokine genes investigated included Interleukin-18 (IL-18), IL-18 receptor alpha (IL-18Rα) and Tumour Necrosis Factor alpha (TNF-α). Sequencing of MSP-2 gene and of the pro-inflammatory cytokines was carried out using ABI PRISM® 3100. Sequences were analyzed using the BioEdit Sequence Alignment software. Genotype and allelic frequencies were analyzed by Chi-square test. The level of significance was set at P=0.05. All participants had P. falciparum infection. Polyclonality was significantly higher in the AS (61%) and UM (60%) groups compared with the SM (34%) group. Mean multiple infections was 2.1 ±1.0 in AS, 2.0 ±1.0 in UM and 1.3 ±0.6 in SM. A total of 32, 35 and 28 distinct MSP-2 alleles were found in the AS, UM and SM groups respectively. Frequency of the 3D7 allele type was significantly higher in UM (51%) and SM (54%) groups compared to the AS group (38%). Sequence analysis of the central variable region of the MSP-2 gene showed that the FC27-type sequence was characterised by two unique subtypes and hybrid sharing sequence with the two subtypes. The 3D7-type sequence was characterised by three subtypes of repetitive domains: a GSA-rich repeat unit, a TPA repeat motif and a poly-Threonine stretch. Three single nucleotide polymorphisms (SNPs): -656G/T, -607C/A and -137G/C were identified at the promoter region of IL-18 gene. The -656G/T and -607C/A SNPs were found to be in complete linkage disequilibrium. The genotype frequency of -607AA was significantly higher in the AS group compared to SM cases (χ2=4.26, P<0.05). Likewise, four SNPs were identified at the promoter and Exon 1 of the IL-18Rα: -661T/C, -175G/A, -93C/T and Ex1 +21C/G but none was associated with disease outcome based on statistical level of significance. Exons 2 to 11 of IL-18Rα gene were relatively conserved. Furthermore, two SNPs: -308G/A and -238G/A were identified at the promoter region of TNF-α but none was associated with disease outcome. Plasmodium falciparum was found to be genetically heterogeneous. Higher carriage of Plasmodium falciparum 3D7 alleles indicates higher risk of developing symptomatic malaria. There was association between IL18 -607AA genotype and asymptomatic infection, probably indicating a protective role.Item GENETIC POLYMORPHISMS ASSOCIATED WITH HYPERTENSION IN THE ETHNIC POPULATIONS OF CALABAR AND UYO, NIGERIA(2012-08) KOOFFREH, M.EHypertension is a public health challenge due to its high prevalence, and is a major risk factor for cardiovascular diseases. Hypertension is a complex disease resulting from an interaction of genes and environmental factors. Inconsistent association between polymorphisms of the renin angiotensin aldosterone, the atrial natriuretic peptide systems and hypertension has been reported among various ethnic groups, but not for the Efiks and Ibibios in south-south Nigeria. This study was designed to determine the frequency of gene polymorphisms of these two systems and their association with hypertension in Calabar and Uyo, Nigeria. A population-based case control design was used. A total of 1224 participants, 612 each of patients and controls were randomly recruited from hypertension clinics and the general population. Genotyping of the M235T allele of the angiotensinogen, Insertion/Deletion allele (I/D) of the angiotensinogen converting enzyme, A1166C allele of the angiotensin II type I receptor and C664G allele of the atrial natriuretic peptide genes to identify variants was performed using polymerase chain reaction and restriction enzyme digestion. The Hardy-Weinberg equation was used to calculate the allele and genotype frequencies. Plasma angiotensinogen levels were measured by Enzyme Linked Immunosorbent Assay. Hypertensinogenic factors such as age, familial history, physical exercise and drinking were assessed using questionnaires. Descriptive statistics, chi-square, multiple regression analysis and odds ratio were used to analyze the data. The frequency of the genotypes M235M, M235T, T235T of the M235T allele for the Efiks were 0.4, 7.7, 92 % in patients and 0, 6, 94 % in controls; for the Ibibios were 0.5, 1.2, 87 % in patients and 0, 7, 93 % in controls. The I/D genotypes II, ID, DD frequencies for the Efiks were 11, 44, 46 % in patients and 16, 45, 39 % in controls; for the Ibibios were 11, 40, 49 % in patients and 13, 49, 38 % in controls. The frequency of the A1166C carriers was 1 % while 99 % of the study population had the wild type A1166A genotype for the A1166C allele. Only the CC genotype was observed for the C664G allele. These frequencies did not conform to the Hardy-Weinberg assumptions. There were no significant differences between the genotype frequencies of patients and controls. Plasma angiotensinogen values were significantly higher in the patients with M235T allele than in the controls. Age was a positive predictor for systolic blood pressure (SBP, r = 0.60) in patients and diastolic blood pressure (DBP, r = 0.56) in controls. Other hypertensinogenic variables were not predictors for SBP and DBP in the population (p < 0.05). The Insertion/Deletion allele was a risk factor for hypertension, (O.R = 1.15). A high frequency was observed for the M235T allele and the Insertion/Deletion allele, which was associated with an increased risk for hypertension. The lack of association between the alleles of the M235T, A1166C and the C664G and hypertension suggests that other loci or environmental factors are involved in the disease outcome.