Tumor Necrosis Factor-Like Ligand 1a (TL1A) is a cytokine encoded by Tumor Necrosis Factor Super Family 15 gene (TNFSF15) gene mostly in endothelial cells which binds to T-cells and foments the production of pro-inflammatory cytokines including TNF-α, IL-6, IL-1b, IFN- γ and IL-13. TL1A level is elevated in inflammatory diseases including Crohn's Disease (CD). Although Single Nucleotide Polymorphisms (SNPs) in TNFSF15 have been reported in CD, no studies have investigated the effect of these SNPs on TL1A, inflammation, and susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. MAP is a strong candidate in CD pathogenesis. This study is designed to elucidate the combined effect of MAP and SNPs in TNFSF15 (rs4263839, rs7848647, rs6478108, or rs6478109) on TL1A secretion and downstream effect on pro-inflammatory cytokines. Peripheral blood from CD and healthy subjects was analyzed for MAP DNA, TNFSF15 genotyping, circulating TL1A level, and IFN- γ and TNF-α gene expression. Our data is first to report that rs4263839, rs7848647, rs6478108, and rs6478109 in TNFSF15 resulted in increase in circulating TL1A level in healthy and CD samples. Specifically, in CD samples with rs7848647, the average TL1A level was 146.9 pg/mL ± 124.5 compared 62.4 pg/mL ± 82.8 in normal samples. Similarly, TL1A level in CD samples with rs6478109 was 141.9 pg/mL ± 127.7 compared to 71.5 pg/mL ± 88.4 in normal samples (p < 0.05). All 4 SNPs resulted in significant elevation in TL1A level in healthy samples (p < 0.05). Moreover, IFN-γ expression was significantly higher, by approximately 1.6-fold in CD patients with SNPs relative to CD patients with no SNPs (p < 0.05). Interestingly, SNPs in TNFS15 had no significant effect on TNF-α expression. MAP was detected in the blood of 63% of CD compared to 6% healthy subjects (p < .001). The data did not support a correlation between MAP presence and circulating TL1A levels, and no correlation between SNPs in TNSF15 and MAP susceptibility. This study strongly suggests, that SNPs in TNFSF15 increase TL1A levels and may be a contributory factor to the inflammation experienced by CD patients. Over all, the study emphasizes the need for a pharmacogenomic approach in treatment delivery for patients with CD by using TNFSF15 SNPs to identify patients that would benefit from biologics targeting TL1A rather than TNF-α for more efficacious treatment regiments for CD patients.
Master of Science (M.S.)
College of Medicine
Length of Campus-only Access
Masters Thesis (Open Access)
Hassouneh, Sayf Al-Deen, "Role of Mycobacterium avium paratuberculosis (MAP) and TNFSF15 SNPs on TL1A in CD" (2018). Electronic Theses and Dissertations, 2004-2019. 5947.