Lower respiratory tract infections (LRTIs) are one of the most common infectious diseases in Europe and worldwide. Very little is known about the genetic factors associated with susceptibility to LRTI and so far studies have only analysed candidate gene loci. This work aimed to find genetic loci associated with susceptibility to severe and mild LRTI. To analyse severe LRTI, a European cohort of community acquired pneumonia (CAP) sepsis patients was used. To analyse mild LRTI, patients attending primary care with a cough were recruited across Europe. Two important candidate genes for susceptibility to severe and mild LRTI were studied. None of the four functional polymorphisms analysed in MBL2 were associated individually or when combined with susceptibility to LRTI or survival from severe LRTI. Rare homozygotes for rs12252 in the IFITM3 gene were found to associate with susceptibility to mild and severe viral LRTI, particularly influenza infection. Using a combination of genome-wide and candidate gene methods, 93 single nucleotide polymorphisms (SNPs) were chosen to genotype and analyse for susceptibility to mild LRTI. A gene region containing the MPHOSPH8, TPTE2, PSPC1 and ZMYM5 genes was found to associate with susceptibility to rhinovirus infection. A functional promoter SNP in the IL6 gene and a gene region containing the SAP18, MRP63 and SKA3 genes were associated with susceptibility to mild LRTI in smokers. A GWAS was performed for susceptibility to CAP sepsis in Europe. Genotypes were imputed for eight GWAS data sets comprising over 1000 CAP sepsis cases and over 4000 controls. Preliminary analysis results suggest an association in a chromosome 1 region containing the genes VASH2, ANGEL2 and RPS6KC1. This thesis presents results of the largest known genetic association study for susceptibility to CAP sepsis, and the only known genetic association study for mild LRTI. These novel findings will facilitate further research which may lead to better treatment and outcome for LRTI.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:588391 |
| Date | January 2012 |
| Creators | Mills, Tara Carolyn |
| Contributors | Hill, Adrian V. S.; Rautanen, Anna |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:fc88b1f2-5930-46cd-a196-761301b7cb29 |
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