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

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 A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A.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 8

TCR gene correlations with psoriasis-associated cytokines.

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TCR gene correlations with psoriasis-associated cytokines. (A) Correlati...
(A) Correlation of gene expression of TRB within psoriatic plaques with psoriasis-associated cytokines in the discovery RNA-Seq dataset (Tsoi et al. dataset details [32] listed in Table 6). Spearman correlation coefficients and P values are displayed on each plot. P values for Spearman’s test were calculated using the asymptotic t approximation. Significant correlations are outlined in blue. (B) Paired correlation analysis (psoriasis lesion versus matching nonlesion samples) in discovery RNA-Seq dataset. Differences in gene expression were calculated (normalized gene expression of nonlesion samples were subtracted from normalized gene expression of matching lesion samples). Then, the Spearman correlation coefficient was calculated for the difference in gene expression. Correlation coefficients and P values are displayed on each plot. P values for Spearman’s test were calculated using the asymptotic t approximation. Significant correlations (P < 0.05) are outlined in blue. (C) Waterfall plots depicting IL-17A correlations for all TRAJ and TRGV gene segments in discovery RNA-Seq dataset. Differences in gene expression were calculated (normalized gene expression of nonlesion samples were subtracted from their corresponding values of matching lesion samples). Then, Spearman correlation coefficients for differences in gene expression were calculated. Spearman correlation coefficients are depicted on the y axis. TRAJ or TRGV gene segments are separated on the x axis. P values for Spearman’s test were calculated using the asymptotic t approximation. Significant correlations (P < 0.05) are highlighted in blue.