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Title: The genetics of susceptibility to tuberculosis and leprosy in a Brazilian population
Author: Jamieson, S. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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The region of conserved synteny on mouse chromosome 11/human 17q11.2-q22 has been identified as carrying susceptibility genes for intramacrophage pathogens. This region contains numerous candidate genes including, NOS2A encoding inducible nitric oxide synthase, the β-chemokine gene cluster (including CLL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES), CCR7 encoding the receptor for CCL19/CCL21, and genes for signal transducers and activators of transcription STAT3 and STAT5A/5B. To determine the role of this region in susceptibility to mycobacterial infection, 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from North-Eastern Brazil have been investigated using 15 polymorphic mirosatellites and 49 informative single nucleotide polymorphisms (SNPs). Multipoint non-parametric analysis of the microsatellite markers in ALLEGRO showed suggestive evidence for linkage with two peaks for leprosy at D17S250 (Zlr score 2.34; p=0.01) and D17S1795 (Zlr score 2.67; p=0.004) and a single peak for tuberculosis at D17S250 (Zlr 2.05; p=0.02). Combined analysis for a general mycobacterial susceptibility gene provided significant evidence for linkage with a peak Zlr (3.38) at D17S250, equivalent to an allele sharing LOD score of 2.48 (p=0.0004). To determine whether one or multiple genes are contributing to disease susceptibility, 49 informative SNPs were typed in all candidate genes. Family-based allelic association testing that was robust to family clustering confirms that polymorphisms at four loci, NOS2A, CCL18, CCL4 & STAT5B, or genes in linkage disequilibrium with them, are contributing to TB susceptibility in this population. Furthermore, results demonstrate that polymorphisms at CCL18 and STAT5B, or genes in linkage disequilibrium with them, may also be contributing to the tuberculoid form of leprosy. These results follow the trend that initial linkage peaks in complex traits such as infectious disease susceptibility result from clusters of functional genes/polymorphisms and identify 17q11.2-q21 as an existing candidate region for ongoing studies into mycobacterial disease susceptibility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available