284 Identification of psoriasis-protective chemokine, FAM19A5, and IL17D expression in psoriatic skin

Abstract

Psoriasis is a chronic inflammatory skin disease with an estimated heritability of 80%. Susceptibility loci identified by GWAS studies account for a small fraction of this heritability. While gene expression analyses have identified thousands of differentially expressed genes in psoriasis, only a small fraction are likely involved in psoriasis pathophysiology. FAM19A5 is of special interest because it is a chemokine-like molecule that is highly expressed in normal skin but downregulated in psoriatic plaques (p= <2x10-16). We therefore sought to mine psoriasis RNA-Seq datasets to identify other genes associated with FAM19A5 and to determine if this gene is related to psoriasis susceptibility. Correlative analysis identified a dependent relationship between FAM19A5 and IL17D (r= 0.64, p= 3.2x10-13). IL17D was also found to be downregulated in psoriasis (p= <2x10-16). A nonlinear dimensionality reduction strategy illustrated a close spatial relationship between FAM19A5 and IL17D, which mapped away from the proinflammatory cytokine cluster of IL17A, IL23A, IL36, and IL1B. We also identified an IL17D-associated allele (rs9509353) that was protective against psoriasis (OR= 0.20, p= 5.9x10-7) and a protective variant of FAM19A5 (rs131959; OR= 0.29, p= 8.8x10-5). Both protective variants were associated with increased FAM19A5 expression (p= 6.1x10-4 and 7.8x10-5). Similar to the results in the setting of human psoriasis, IL-23 minicircle-induced psoriasis-like dermatitis in B6 mice demonstrated striking downregulation of FAM19A5 compared to controls (>20 fold decrease). These results highlight a putative regulatory role for FAM19A5 and IL17D in psoriasis and IL17D as an upstream regulator of FAM19A5 expression.