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Title: Genetic susceptibility to common mycobacterial diseases
Author: Wong, Hei Sunny
ISNI:       0000 0004 2694 6347
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2010
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Common mycobacterial diseases, including tuberculosis and leprosy, contribute to major mortality and morbidity worldwide. Despite evidence of an important role of host genetic factors in susceptibility to these infections, few compelling genetic associations have been identified with previous candidate gene and linkage approaches. This thesis investigates the genetic factors of human immunity to these mycobacterial diseases using a high-throughput approach of association testing. To assess genetic susceptibility to tuberculosis, I have conducted a genome-wide association study in the Gambian population as part of the Wellcome Trust Case Control Consortium (WTCCC). The study reveals the region flanking CADM1 as a potential susceptibility locus. Combining this study with a Ghanaian cohort further implicates two genetic loci at chromosome 18q11.2 (P = 9.2x10⁻⁹) and PARD3B (P = 1.4x10⁻⁶). For leprosy, I have performed a gene-centric association study in the New Delhi Indian population. Evidence of significant association was observed in the HLA-DRB1/DQA1 (P = 4.9x10⁻14) and TLR1 (P = 1.7x10⁻⁹) loci. These studies identify important genomic regions that may be involved in immunity to tuberculosis and leprosy. Further analysis revealed a significant immunogenetic overlap between tuberculosis and leprosy. This provides proof-of-principle for the subsequent aggregate analysis for mycobacterial susceptibility, which suggests that the steroid biosynthesis pathway may be important in anti-mycobacterial immunity. This thesis represents one of the largest studies to identify the genetic factors for human immunity against mycobacteria. These novel findings will further enhance vaccine and pharmaceutical efforts into prevention and treatment of these mycobacterial diseases.
Supervisor: Hill, Adrian Vivian Sinton Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medical Sciences ; Clinical genetics ; Infectious diseases ; Biology (medical sciences) ; Genetics (medical sciences) ; Evolution (zoology) ; genetics ; susceptibility ; mycobacteria ; tuberculosis ; leprosy