Psoriasis: a study of the skin transcriptome and microbiome

Ceylan Ece Tanes

doi:10.17918/etd-6392

Psoriasis is a complex autoimmune skin disorder characterized by dry, scaly plaques and painful flares. Even though genetic contribution and environmental factors are suspected, the exact trigger of psoriasis is not well understood. The chronic condition of the disease and the lack of effective and definitive treatments are burdens on the patients. Recent emergence of transcriptome and genomic datasets for the host, as well as the taxonomic datasets for the microbiome has enabled the use of bioinformatics approaches to investigate altered gene circuits in psoriasis. As a first step, open source microarray datasets of psoriasis were analyzed in context of other skin conditions. The analysis showed that upregulated genes in the psoriasis transcriptome included those involved in epidermal differentiation complex and antimicrobial processes, while the top downregulated genes were involved in lipid metabolism. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were enriched with significantly altered genes point to the upregulation of both innate and adaptive immune responses. The psoriasis gene signature was distinctive from other inflammatory skin conditions and it resembled the wound healing process in terms of keratinization and immune response signals. On the microbiome side, over-abundance of opportunistic bacteria on the psoriasis microbiome was observed compared to controls. Virulence genes were consistently in high abundance across different body sites. Bacterial invasion of epithelial cells gene pathway was crowded with both significantly altered genes on the host side and high-abundance orthologs on the microbiome side. The findings suggested bacterial involvement in the initiation or maintenance of psoriasis flares. Genetic components also play a role in susceptibility to psoriasis. Human Leukocyte Antigen (HLA) is one of the regions that has previously been associated with psoriasis through Genome Wide Association studies. The Single Nucleotide Polymorphisms (SNPs) typed in the HapMap dataset (11 ethnic populations) within the HLA region have been analyzed using extended haplotype homozygosity based tests to identify positive selection on polymorphisms that have not yet reached fixation. Results showed regional specificity of positive selection signals on the sub-classes of HLA. The positive selection signals in Class I sub-region showed European ancestry specificity with intronic SNPs on a psoriasis related gene PSORS1C1 as well as on TCF19, MUC22, TRIM10, and TRIM15. The region specific selection signals were also seen in the Class III region for the East Asian populations and in the Class II region for African ancestry populations. Similar to single population tests, the cross population tests showed that the significant SNPs were concentrated in the Class II region for African ancestry populations, whereas for European ancestry populations, they were concentrated in the Class I region. The results show how positive selection of a SNP can encourage genetic hitchhiking of the susceptibility SNPs for a disease along with a SNP that is under positive selection. This research thesis bridges large scale transcriptome datasets of the host and operational taxonomy unit abundance datasets of the microbiome, opening up new avenues for drug repositioning studies by pointing out specific host-microbiome genes as drug targets.

Psoriasis: a study of the skin transcriptome and microbiome

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Psoriasis: a study of the skin transcriptome and microbiome

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