The worldwide rates of asthma have been increasing in the past twenty years, coinciding with a decreasing prevalence of tuberculosis in the major asthma endemic regions. The hygiene hypothesis proposes that in countries with better hygiene, reduced exposure to pathogens is responsible for the rising prevalence of allergic diseases. Mycobacterium tuberculosis , the cause of tuberculosis (TB), is thought to be a critical effector of the hygiene hypothesis since it can skew the immune system away from developing into an atopy associated immune profile. Hence, absence of exposure to M. tuberculosis might remove suppression of asthma development. / Based on the hygiene hypothesis, we reasoned that genetic factors that predispose to TB should be protective for asthma/atopy and vice versa. Consequently, we tested genetic variants for (1) asthma risk based on known genetic effects in TB susceptibility, and (2) TB risk based on known genetic effects in asthma susceptibility. To identify genetic variants for asthma risk, we tested for nonrandom transmission of genetic variants of the Vitamin D Receptor (VDR) and the Natural Resistance Macrophage Protein 1 (NRAMP1) genes, two known TB susceptibility genes, in an asthma family-based cohort of French Canadian. To identify genetic variants for TB risk, we tested for distribution differences of genetic variants of several asthma associated genes: interleukin 4 (IL-4), IL-4 Receptor A (IL4RA), tumour necrosis factor A (TNFA ), lymphotoxin A (LTA) and VDR in TB cases and non-TB controls recruited in Mexico. Only VDR variants showed a risk modulating effect and where analyzed in more detail in the present thesis. / In a North-Eastern Quebec asthma family-based cohort, of the 12 VDR variants tested 6 genetic variants located between intron 2 and 3' UTR we found to be strongly associated with asthma (0.0005 < p < 0.01) under an additive model. Haplotype specific genetic effects were also observed for asthma (0.0004 < p < 0.01). By contrast, no variants of the NRAMP1 gene were observed to be associated with asthma in this French Canadian asthma cohort. In the final set of experiments, I tested asthma associated genes for their impact on risk of TB disease. In a Mexican case-control study, 14 VDR variants tested, we observed 2 genetic variants at the 5' end of the gene to be associated (p < 0.05) with either susceptibility to TB, M. tuberculosis infection or disease progression. No associations were observed between genetic variants of IL4RA, TNFA and LTA, and TB or TB related phenotypes. / These findings clearly identified VDR as asthma and TB susceptibility gene. However, since the genetic variants associated with asthma differ from those associated with TB it remains unclear how these variants influence the immune system to promote asthma but not TB, and vice versa. Although TB has been proposed as a suppressing force for asthma, other than VDR, we could not detect any genetic effect of TB susceptibility genes in the asthma study, nor effects of asthma susceptibility genes in the TB study. We interpret these findings as evidence against counter-selection of asthma and TB susceptibility gene variants.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85953 |
| Date | January 2005 |
| Creators | Poon, Audrey Ho Yee |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002260859, proquestno: AAINR21690, Theses scanned by UMI/ProQuest. |
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