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Title: A genetic epidemiological study of prevalence and association of genetic polymorphisms in asthma related phenotypes among children in Durban, Kwazulu-Natal
Authors: Makamure, Michelle 
Issue Date: Dec-2012
Several genes are associated with an increased susceptibility to respiratory diseases, including asthma, which may be exacerbated by ambient air pollution. These genes include the Tumour Necrosis Factor alpha (TNFα) gene and the Cluster of Differentiation 14 (CD14) gene A total of 104 schoolchildren from seven primary schools in a heavily industrialized region of south Durban participated in the study. For the purpose of this study, DNA was extracted from whole blood using the GENTRA Puregene kit. Genotyping for the TNF-308α G/A polymorphism was conducted using restriction fragment length polymorphism (RFLP) polymerase chain reaction (PCR). The CD14 (-159) C/T genotype was determined using real time PCR and Taqman probes (Applied Biosystems). Multiple logistic models and Pearson’s chi-squared tests were used to evaluate the association between any asthma, BHR, atopy, persistent asthma and genotype. Covariate-adjusted generalised estimating equations (Martin et al.) with lags of 1-5 days were used to evaluate genotype effect modification of exposure-response. The TNF-308α variant A allele was quite common in the population, it was detected in more than forty percent of the population and with an allelic frequency of 0.24. Similarly almost 38% of the population carried the variant CD14 (-159) T allele, with an allelic frequency of 0.24. TNF-308α G/A and CD14 (-159) C/T polymorphisms were not associated significantly with asthma, and its related respiratory phenotypes. In addition there was no association detected between any of the gene polymorphisms and the levels of their respective cytokine proteins. Increased TNFα levels were associated with persistent asthma. On the other hand lower sCD14 levels were associated with atopy in children. There was a significant relationship between TNF- α levels and acute asthma (p=0.03) and sCD14 levels and atopy (p=0.04) GEE models showed that the TNF- 308-α A allele carriers had a greater deterioration of lung function post pollution exposure to SO2 (intraday variability FEV1 readings lag 2) β= 2.62, CI (0.51, 4.71) p= 0.02 and p (interaction=0.03). There was a statistically significant gene environment interaction with NO in individuals who were carriers of the TNF- A allele (Nadir of PF readings lag 2: β= -12.3, CI (-22.09, -2.51), p=0.01 p (interaction) =0.03.and 5 day average β= - 42.83, CI (-70.11,-15.55), p≤0.005 and p (interaction) =0.01). With analysis of the CD14 gene polymorphism gene environment interaction, adverse effects of SO2 were limited to individuals carrying the C allele of this polymorphism, β= - 1.50, CI (-0.36, 3.37), p=0.01, p (interaction) =0.01. Carriers of the T allele seemed to have a protective effect with NO2 and NO exposure. Intraday variability of FEV1 improved 5 days post exposure to NO2 β= -4.02, CI (-6.52,- 1.53), p=0, p (interact) =0.05. There was also improvement five days post exposure to NO β= -9.42, CI (-12.45, -6.03), p= p≤0.005, p (interact) ≤0.005 There was no association of co-inheritance of the 2 gene polymorphisms, CD14 (-159) C/T and TNF-308α G/A, and protein expression or respiratory phenotype. The GEE model results were consistent with modification of air pollutant-pulmonary function relationships by proinflammatory cytokine associated genotypes. Results indicate that genetic susceptibility combined with exposure to pollutants causes adverse respiratory effects. This study supports the importance of further investigation on these and other genotype variants involved in inflammation and respiratory linked phenotypes in larger cohorts.
Submitted in fulfillment of the requirements for the degree of Master of Technology: Health Sciences, Durban University of Technology, Durban, South Africa, 2013.
Appears in Collections:Theses and dissertations (Health Sciences)

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