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 A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A.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

Meta-analysis of RNA-Seq datasets to confirm psoriasis associations with overexpression of TRAJ23 and decreased expression of TRAJ39.

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Meta-analysis of RNA-Seq datasets to confirm psoriasis associations with...
(A) Using an independently acquired second sample set (Weidinger dataset details are listed in Table 6) as a validation sample set the proportionate TCR gene segment usage was determined for separately pooled psoriasis and healthy samples. 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 6. Gene segments statistically significantly elevated in the first (Tsoi et al. dataset details [32] are listed in Table 6) dataset are designated with an arrow on the graph. (B) Meta-analysis of RNA-Seq datasets comparing psoriasis versus healthy skin. Forest plots of the standardized mean difference of proportionate TCR gene segment expression in psoriasis lesional skin versus healthy controls. 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.