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

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

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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 A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A.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 6

Increased αβ TCR repertoire diversity in psoriasis.

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Increased αβ TCR repertoire diversity in psoriasis.
(A) In silico CDR3 s...
(A) In silico CDR3 spectratyping (distribution of clonotype frequency by CDR3 length) for the β and α chains. TCR CDR3 sequences were extracted from RNA-Seq datasets using MiXCR software, and reads for healthy (blue bars) and psoriatic individuals (red bars) were pooled. CDR3 sequence length is plotted along the x axis. The abundance of the TCR sequences is plotted on the y axis. The Shannon diversity index was then calculated for healthy (blue dots) and psoriatic (red dots) CDR3 sequences, and Wilcoxon rank sum test was used to estimate statistically significant differences in diversity; tabulated results are provided in Supplemental Table 10. Finally, a meta-analysis across all RNA-Seq datasets was used to verify the finding that psoriasis is associated with increased TCR CDR3 diversity. Forest plots of the standardized mean difference of TRB CDR3 diversity (psoriasis versus healthy control and psoriasis lesion versus nonlesional skin) are shown. Each black box is representative of the study weight for each data set, and horizontal lines are 95% CI. Diamonds represent standardized mean differences for results of all studies combined. Extremes of diamonds give 95% CI. (B) Full and partial CDR3 sequences from reads containing TRAJ23 were extracted using MiXCR or TCRminer. Amino acid sequences were analyzed using R package tcR. Common TRAJ23-encoded 5-mer sequences are presented. Both MiXCR and TCRminer yielded similar sequences, which did not differ significantly between psoriasis and healthy controls.

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