PHARMACOGENETICS AND PHARMACO-EPIGENETICS OF TUMOR NECROSIS FACTOR-ALPHA INHIBITORS IN RHEUMATOID ARTHRITIS IN QATAR

Abstract

Heterogeneity in therapeutic response to tumor necrosis factor inhibitors (TNFi) remains a major clinical limitation in the management of autoimmune diseases, such as rheumatoid arthritis (RA). This doctoral dissertation aims to elucidate the molecular determinants underlying the variation in response to TNFi using a multi-omics framework, including genome-wide association testing, transcriptomic and CUT&RUN histone mark profiling of isolated T cells, and genome-wide DNA methylation profiling of whole blood in an adult RA cohort from Qatar. This cohort represents South Asian and Middle Eastern populations, which are largely absent from prior pharmacogenomic (PGx) studies, thereby addressing a significant gap in the field. A novel genome-wide significant association was identified within TMC7, a gene not previously linked to TNFi response or immune-related diseases. The reference allele (G) was associated with improved TNFi response, possibly via altered expression in response to TNF-α–mediated inflammatory signaling and/or regulation of mechano-sensation pathways. Several additional variants reached suggestive significance, including an independent association in the TMC7 locus that mapped to COQ7. Transcriptomic analysis identified 131 differentially expressed genes (DEGs) between responders (R) and non-responders (NR), most of which have not been previously reported in relation to TNFi response but are biologically relevant. MDGA1 and AK5 were lower expressed, while MSR1, FRP1, TNFAIP3 and S100A8 were overexpressed in NR. TGM2, IFNG, and IL1RN were marked as the top upstream driving regulators, proposing a TNFα independent signaling behind the failure of TNFi response. The histone mark profiling provided supporting evidence for several DEGs. DNA methylation did not reveal significant differentially methylated sites, but the enrichment analysis suggests early epigenetic programming, particularly in CD34+ progenitor cells, that may influence immune-cell behavior in the context of TNFi response. In summary, this dissertation reveals new genetic, transcriptional, and epigenetic contributors to TNFi response in RA. Despite limitations, our findings add to the current understanding of TNFi PGx, emphasize the importance of studying under-represented populations, and provide a foundation for future mechanistic and translational studies for validation and implementation of precision medicine approaches in rheumatoid arthritis at a later stage.

Date of Award	2026
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences