Abstract
Mycetoma is a chronic inflammatory infection that can lead to severe disability by damaging the skin, soft tissues, and bones if left untreated. It is one of the neglected tropical diseases (NTDs) caused by either bacteria (actinomycetoma) or fungi (eumycetoma). Sudan has one of the highest disease burdens globally, with eumycetoma responsible for 70% of infections.Genetic factors likely influence susceptibility, evidenced by familial clustering. However, to date, genetic studies have focused on a pre-defined set of functional polymorphisms in 13 candidate genes selected for their involvement in immunity. All previous studies were among small sample-sized cohorts, and positive findings have not been reproduced. This thesis, therefore, employed a systematic approach beginning with estimating heritability and sibling recurrence risk ratio. Subsequently, two hypothesis-free genomic approaches were utilised: family-based whole-genome sequencing (WGS) and population-based genome-wide association studies (GWAS).
The family-based study involved 46 pedigrees, estimating mycetoma heritability at approximately 23%, with a higher likelihood of occurrence among siblings as indicated by a recurrence risk ratio ranging from 18.4 to 28.7. To identify rare genetic variants present in affected individuals but not in their healthy family members, 22 individuals from four families with multiple cases of mycetoma were selected for WGS. This analysis identified four candidate genes: DEFA3, CASP8, PLEKHO2, and RAPGEF2. Subsequently, network and pathway analyses emphasised the candidate genes’ interconnectedness within crucial pathways such as the immune system and signal transduction. The population-based GWAS identified 15 suggestive associations, with rs16861260, rs319883, and rs10520048 associated with lower susceptibility, while in silico functional analyses of the identified genetic markers revealed pathways related to lymphocyte function and migration regulation. The genotyping data also showed a significant proportion of the disease's heritability attributed to common genetic variants, which accounted for nearly 80%. The high rate of consanguinity within the Sudanese population, as evidenced by a genomic inbreeding coefficient of 0.0317, highlighted the persistent impact of cultural practices on genetic diversity. Finally, The study emphasised the superiority of African ancestry reference panels for genotype imputation of Sudanese datasets.
This thesis marks the first-ever attempt to investigate the genetics of susceptibility to mycetoma systematically. It collectively advances our understanding of mycetoma's genetic basis, providing valuable insights for future investigations and potentially informing targeted interventions.
| Date of Award | Feb 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Melanie Newport (Supervisor) & Dr Sahar Mubarak Bakhiet (Supervisor) |