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 Gluthathione-S-Transferase family (GSTM1 and GST1l) and the NAD(P)H quinone oxidoreductase (NQO1). This, the first genetic epidemiological study conducted in Sub-Saharan Africa had 2 main objectives: I) to evaluate whether the above genotypes confer susceptibility to asthma and related phenotypes; and 2) to investigate if polymorphisms in these genes known to modulate the response to or protect from epithelial oxidative damage modify pulmonary response to ambient air pollutants. A total of 369 schoolchildren from seven primary schools in a heavily industrialized
region of south Durban and a demographically similar area in north Durban, Kwa-Zulu Natal, South Africa during the period May 2004 - October 2005, participated in the study. DNA was extracted from whole blood using the GENTRA Puregene kit. Genotyping for the GSTM1 (null vs present genotype) was done using multiplex PCR while the GSTP1 (I1e105Val; AA>AG/GG) and the NQO1(Pro/Ser; CC>CT/TT) genotypes were determined using real time PCR and Taqman probes (Applied Biosystems). Persistent asthma and asthma of "any severity" was determined by questionnaires based on the ATS and BRMC questionnaires. Positive atopy was determined by at least one positive skin test reaction to the seven allergens tested. Other health assessments included spirometry, methacholine challenge testing and four cycles of three-week serial peak flow measurements. Acute respiratory measures included within day variability in FEV1 and PF and the lowest valid values on a given day. SO2. NO2, NO and PM10 were measured over a year using ultraviolet fluorescence, gas-phase chemiluminescence and gravimetric
methods respectively. STATA (version 9, College Station, TX, USA) was used for data analysis. Multiple logistic models and Pearson's chi-squared tests were used to evaluate the association between asthma, BHR, atopy and genotype. Covariate-adjusted generalised estimating equations (GEE) with lags of 1-5 days were used to evaluate genotype effect modification of exposure-response.
The GSTM1 gene deletion (GSTM1null) was detected in 28.9% of the study population while the distribution of GSTP1 AG/GG and the NQO1 CT/IT polymorphisms were 64.9% and 36.0% respectively. Multiple regression with the adjustment for relevant covariates indicated that individuals carrying one or more copies of the GSTP 1 minor allele had a statistically significant risk for persistent asthma. GSTM1 and NQO1 genotypes showed no significant association with any of the respiratory outcomes tested. However, we found a protective effect for those individuals carrying the GSTM1null genotype and at least one Ser allele (NQO1 CT/TT) for persistent asthma and marked
BHR (OR = 0.7, Cl: 0.3-1.5 and OR= 0.3, Cl: 0.0-1.9 respectively). This protective effect is consistent with the role of NQO1 in metabolic activation. Children from the south schools had almost twice the risk of persistent asthma (OR=2.0, Cl: 1.2-3.2, p<.005) and 3 times the risk of BHR (OR=3.5, Cl: 1.4-8.4, p<.005) than those from the schools in the north. Based on symptoms, 20.4% of children from the random sample had persistent asthma and 10.3% had marked BHR (PC20< 2mg/ml). The GEE model results were consistent with modification of air pollutant-pulmonary function relationships by oxidative stress associated genotypes. Statistically significant gene*environment interactions with NO2, NO, and PM10 using FEV1 and PEF outcomes in the expected direction were more frequent for GSTP1 AA and NQO1 CC genotypes
(interaction p-values <0.05). There were very few gene*environment interactions for SO2 and any of the 3 SNPs tested. The most striking finding in our study was that pollutant exposure, especially oxides of nitrogen and PM10, even at levels below the recommended limits of South African guidelines, is associated with poorer lung function and that this association is significantly modified by an individual's genotype, particularly the GSTMlnull, GSTPIAA and NQOICC genotypes. Children with the GSTMlnull GSTPI AG/GG, GSTPI AG/GG NQOI CC and GSTMlpos NQOICC gene-gene combinations showed a significant interaction with NO2, NO, and PM10 with decrement in lung function measures. The increased risk to air pollution conferred by the GSTPI and GSTMl genotypes may have clinical and public health importance because this variant is common in most populations. The findings suggest that the risk of developing respiratory symptoms is increased when genetic susceptibility is included with environmental exposures. Our models suggest significant gene*environment interactions i.e the response to the level of air pollutants, as indicated by variability in pulmonary function measures, is modified by genotype. The heightened allergic airway response may be a consequence of a decreased capacity to mount an effective cytoprotective response to oxidative stress. Studying genes may inform us about the biology of asthma which may lead to new therapies or preventative strategies. This study supports the importance of further investigation on these and other genotype variants involved in oxidative stress and respiratory phenotypes in larger cohorts. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2008.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/2218 |
| Date | January 2008 |
| Creators | Reddy, Poovendhree. |
| Contributors | Naidoo, Rajen., Naidoo, Richard. |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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