Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A
Alexander A. Merleev, … , Michiko Shimoda, Emanual Maverakis
Alexander A. Merleev, … , Michiko Shimoda, Emanual Maverakis
Published July 12, 2018
Citation Information: JCI Insight. 2018;3(13):e120682. https://doi.org/10.1172/jci.insight.120682.
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Research Article Dermatology Genetics

Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A

Abstract

Numerous studies of relatively few patients have linked T cell receptor (TCR) genes to psoriasis but have yielded dramatically conflicting results. To resolve these discrepancies, we have chosen to mine RNA-Seq datasets for patterns of TCR gene segment usage in psoriasis. A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A. TRGV5, a TCR-γ segment, was also associated with psoriasis but correlated instead with IL-36A, other IL-36 family members, and IL-17C (not IL-17A). In contrast, TRAJ39 was strongly associated with healthy skin. T cell diversity measurements and analysis of CDR3 sequences were also conducted, revealing no psoriasis-associated public CDR3 sequences. Finally, in comparison with the expression of TCR-αβ genes, the expression of TCR-γδ genes was relatively low but mildly elevated in psoriatic skin. These results have implications for the development of targeted therapies for psoriasis and other autoimmune diseases. Also, the techniques employed in this study have applications in other fields, such as cancer immunology and infectious disease.

Authors

Alexander A. Merleev, Alina I. Marusina, Chelsea Ma, James T. Elder, Lam C. Tsoi, Siba P. Raychaudhuri, Stephan Weidinger, Elizabeth A. Wang, Iannis E. Adamopoulos, Guillaume Luxardi, Johann E. Gudjonsson, Michiko Shimoda, Emanual Maverakis

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Figure 1

Patterns of TCR V/J gene usage in the setting of psoriasis.

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Patterns of TCR V/J gene usage in the setting of psoriasis. Tsoi et al. ...
Tsoi et al. dataset details are listed in Table 6 (32). (A) Differential gene expression by DESeq2 (Fold Change on y axis) of TCR TRA gene segments in psoriasis versus healthy controls. TRAJ gene segments are separated on the x axis. Differentially expressed genes (FDR < 0.05) are depicted in bold. (B) To estimate the variation in variable (V) and joining (J) segment usage, all reads mapping to each gene segment were pooled separately for both healthy and psoriatic individuals. The proportions for each TCR gene segment were then calculated (e.g., ratio of TRAJ39 counts to all TRAJ counts). Fisher’s exact test for count data was used to estimate statistically significant differences in the TCR segment usage between healthy and psoriatic samples. Gene segments with FDR < 0.05 and an odds ratio <0.5 or >2 are designated with an asterisk on the graph. Gene segments with statistically significant changes in their proportionate gene expression are listed in Supplemental Table 4. (C) Unpaired analysis of proportionate expression of TCR genes in psoriasis plaques versus nonlesional skin. All reads mapping to each gene segment were pooled separately for both lesional and nonlesional samples. The proportions for each TCR gene segment were calculated as described above. Fisher’s exact test for count data was used to estimate statistically significant differences in the TCR segment usage between lesional and nonlesional skin samples. Gene segments with FDR < 0.05 and an odds ratio <0.5 or >2 are designated with an asterisk on the graph. Gene segments with statistically significant changes in their proportionate gene expression are listed in Supplemental Table 5. Wilcoxon signed rank test for paired samples was used to estimate statistically significant differences.