20.500.12556/DKUM-91297 Single-cell transcriptomic and targeted genomic profiling adjusted for inflammation and therapy bias reveal CRTAM and PLCB1 as novel hub genes for anti-tumor necrosis factor alpha therapy response in Crohn’s disease The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn’s disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression signals, which may be masked due to the treatment or ongoing inflammation; Methods: The singlecell RNA sequencing was performed on PBMC samples from CD patients either naïve to biological therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and independent cohort genomic profiling. Replication and meta-analyses were performed using publicly available raw RNA sequencing files of sorted immune cells and an association analysis summary. Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in CD4+ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds throughout the analyses. An additional assessment proved causal inference of both genes in response to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy or inflammation. inflammatory bowel diseases Crohn’s disease tumor necrosis factor alpha adalimumab single-cell gene expression analysis true false true MDPI Angleški jezik Angleški jezik Znanstveno delo 2024-12-10 11:11:35 2024-12-10 11:24:07 2024-12-11 03:10:49 0000-00-00 00:00:00 2024 0 0 Str. 1-22 Št. 6, št. članka 835 Letn. 16 2024 0000-00-00 Zaloznikova Objavljeno apc 2024-06-11 2024-06-17 2024-06-19 616.3 199620611 10.3390/pharmaceutics16060835 1999-4923 RAZ_Gorenjak_Mario_2024.pdf RAZ_Gorenjak_Mario_2024.pdf 1 4AFD667F7379DDA9424D3CC98E0DB7AA 121434b7ac8739aee5a066d660edf5be40e2ecf49867f68ebc2d621dc594fdc0 9925b495-b6e0-11ef-9a40-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=187232 https://doi.org/10.3390/pharmaceutics16060835 1 251496a6-b6df-11ef-9a40-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=187230 https://www.mdpi.com/1999-4923/16/6/835 1 258bd60b-b6df-11ef-9a40-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=187231 Medicinska fakulteta Fakulteta za kemijo in kemijsko tehnologijo 0 0 0