Genetic basis of immune-mediated susceptibility to infectious disease
Infectious diseases remain a major driver of morbidity and mortality globally. For example, Mycobacterium tuberculosis causes about 10 million cases of tuberculosis (TB) and 1.5 million deaths. In a series of studies I demonstrate that discovering the genetic underpinnings of how immune factors affe...
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| Format: | Thesis |
| Language: | English |
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2015
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| _version_ | 1797108977248501760 |
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| author | Vivek , N |
| author2 | Hill, AVS |
| author_facet | Hill, AVS Vivek , N |
| author_sort | Vivek , N |
| collection | OXFORD |
| description | Infectious diseases remain a major driver of morbidity and mortality globally. For example, Mycobacterium tuberculosis causes about 10 million cases of tuberculosis (TB) and 1.5 million deaths. In a series of studies I demonstrate that discovering the genetic underpinnings of how immune factors affect susceptibility to diseases such as TB reveal new insights into disease susceptibility. Previous transcriptome-wide studies suggested that the ratio of myeloid:lymphoid transcripts was elevated in infants who subsequently developed TB. These data were reminiscent of observations made 80 years ago where the ratio of monocytes:lymphocytes (ML) at time of challenge with mycobacteria, was predictive of survival in animal models. To establish the peripheral blood ML ratio as a novel intermediate phenotype for TB susceptibility, I demonstrated that the ML ratio predicts TB disease in three independent cohorts of adults (n=2207), infants (n=1336) and pregnant women (n=1202). Moreover, in collaboration with others, these findings were extended to other diseases including malaria. Turning attention to the pathophysiologic basis of this association, I found qualitative differences in monocytes according to ML ratio even amongst healthy individuals (n=136), both in functional response to mycobacteria and in transcriptomic profile at rest. Next, I found that the ML and neutrophil:lymphocyte (NL) ratio are highly phenotypically and genetically correlated, suggesting the presence of pleiotropic genetic regulators. I present formal estimates of heritability based on concordance and structural equation modeling of data from twin studies (1664 twin pairs), and amongst unrelated adults (n=5034). A meta-analysis of four genome-wide association studies (total n=5768) was performed as a resource to understand how the ML and NL ratios may be regulated, and to facilitate Mendelian randomization studies. Finally, in a more generalised approach I identified genetic regulators of gene expression in monocytes and neutrophils from healthy adults (n=101) and demonstrated how these give fundamental new insights into a wide array of infectious and non-infectious diseases. Taken together, these studies offer original contributions to the understanding of how genetic factors give rise to immune-mediated susceptibility to infectious disease. |
| first_indexed | 2024-03-07T07:34:02Z |
| format | Thesis |
| id | oxford-uuid:d12d63de-e0e6-4187-a3d3-9d6bc172b302 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:34:02Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | oxford-uuid:d12d63de-e0e6-4187-a3d3-9d6bc172b3022023-02-21T15:38:18ZGenetic basis of immune-mediated susceptibility to infectious diseaseThesishttp://purl.org/coar/resource_type/c_db06uuid:d12d63de-e0e6-4187-a3d3-9d6bc172b302genomicsinfectious diseasesEnglishHyrax Deposit2015Vivek , NHill, AVSMcShane, HMorris, AInfectious diseases remain a major driver of morbidity and mortality globally. For example, Mycobacterium tuberculosis causes about 10 million cases of tuberculosis (TB) and 1.5 million deaths. In a series of studies I demonstrate that discovering the genetic underpinnings of how immune factors affect susceptibility to diseases such as TB reveal new insights into disease susceptibility. Previous transcriptome-wide studies suggested that the ratio of myeloid:lymphoid transcripts was elevated in infants who subsequently developed TB. These data were reminiscent of observations made 80 years ago where the ratio of monocytes:lymphocytes (ML) at time of challenge with mycobacteria, was predictive of survival in animal models. To establish the peripheral blood ML ratio as a novel intermediate phenotype for TB susceptibility, I demonstrated that the ML ratio predicts TB disease in three independent cohorts of adults (n=2207), infants (n=1336) and pregnant women (n=1202). Moreover, in collaboration with others, these findings were extended to other diseases including malaria. Turning attention to the pathophysiologic basis of this association, I found qualitative differences in monocytes according to ML ratio even amongst healthy individuals (n=136), both in functional response to mycobacteria and in transcriptomic profile at rest. Next, I found that the ML and neutrophil:lymphocyte (NL) ratio are highly phenotypically and genetically correlated, suggesting the presence of pleiotropic genetic regulators. I present formal estimates of heritability based on concordance and structural equation modeling of data from twin studies (1664 twin pairs), and amongst unrelated adults (n=5034). A meta-analysis of four genome-wide association studies (total n=5768) was performed as a resource to understand how the ML and NL ratios may be regulated, and to facilitate Mendelian randomization studies. Finally, in a more generalised approach I identified genetic regulators of gene expression in monocytes and neutrophils from healthy adults (n=101) and demonstrated how these give fundamental new insights into a wide array of infectious and non-infectious diseases. Taken together, these studies offer original contributions to the understanding of how genetic factors give rise to immune-mediated susceptibility to infectious disease. |
| spellingShingle | genomics infectious diseases Vivek , N Genetic basis of immune-mediated susceptibility to infectious disease |
| title | Genetic basis of immune-mediated susceptibility to infectious disease |
| title_full | Genetic basis of immune-mediated susceptibility to infectious disease |
| title_fullStr | Genetic basis of immune-mediated susceptibility to infectious disease |
| title_full_unstemmed | Genetic basis of immune-mediated susceptibility to infectious disease |
| title_short | Genetic basis of immune-mediated susceptibility to infectious disease |
| title_sort | genetic basis of immune mediated susceptibility to infectious disease |
| topic | genomics infectious diseases |
| work_keys_str_mv | AT vivekn geneticbasisofimmunemediatedsusceptibilitytoinfectiousdisease |