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Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G
Alexander Merleev, … , Johann E. Gudjonsson, Emanual Maverakis
Alexander Merleev, … , Johann E. Gudjonsson, Emanual Maverakis
Published July 21, 2022
Citation Information: JCI Insight. 2022;7(16):e141193. https://doi.org/10.1172/jci.insight.141193.
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Research Article Dermatology

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G

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Abstract

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a posttranslational regulator of the LDL receptor (LDLR). Recent studies have proposed a role for PCSK9 in regulating immune responses. Using RNA-Seq–based variant discovery, we identified a possible psoriasis-susceptibility locus at 1p32.3, located within PCSK9 (rs662145 C > T). This finding was verified in independently acquired genomic and RNA-Seq data sets. Single-cell RNA-Seq (scRNA-Seq) identified keratinocytes as the primary source of PCSK9 in human skin. PCSK9 expression, however, was not uniform across keratinocyte subpopulations. scRNA-Seq and IHC demonstrated an epidermal gradient of PCSK9, with expression being highest in basal and early spinous layer keratinocytes and lowest in granular layer keratinocytes. IL36G expression followed the opposite pattern, with expression highest in granular layer keratinocytes. PCSK9 siRNA knockdown experiments confirmed this inverse relationship between PCSK9 and IL36G expression. Other immune genes were also linked to PCSK9 expression, including IL27RA, IL1RL1, ISG20, and STX3. In both cultured keratinocytes and nonlesional human skin, homozygosity for PCSK9 SNP rs662145 C > T was associated with lower PCSK9 expression and higher IL36G expression, when compared with heterozygous skin or cell lines. Together, these results support PCSK9 as a psoriasis-susceptibility locus and establish a putative link between PCSK9 and inflammatory cytokine expression.

Authors

Alexander Merleev, Antonio Ji-Xu, Atrin Toussi, Lam C. Tsoi, Stephanie T. Le, Guillaume Luxardi, Xianying Xing, Rachael Wasikowski, William Liakos, Marie-Charlotte Brüggen, James T. Elder, Iannis E. Adamopoulos, Yoshihiro Izumiya, Annie R. Leal, Qinyuan Li, Nikolay Y. Kuzminykh, Amanda Kirane, Alina I. Marusina, Johann E. Gudjonsson, Emanual Maverakis

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Figure 6

PCSK9 expression is negatively and directly related to IL36B and IL36G expression.

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PCSK9 expression is negatively and directly related to IL36B and IL36G ...
(A) Single-cell sequencing of psoriatic nonlesional and lesional skin (n = 9). The UMAP method was used to create 2-dimensional representation of the resulting data. Keratinocyte populations were identified by the expression levels of established keratinocyte markers (red, basal layer keratinocytes, DST high; green, spinous layer keratinocytes, KRT5 low and KLK7 low; and blue, granular layer keratinocytes, KLK7 high). PCSK9- and IL36G-expressing cells are depicted in maroon. (B) Expression of IL36G in individual basal, spinous, and granular layer keratinocytes shown as box-and-whisker plots of log2 transformed gene expression. P values were calculated for each data set using 1-way ANOVA. (C) PCSK9-positive keratinocytes were parsed into 2 groups, PCSK9-high and PCSK9-low (x axis). Box-and-whisker plots of indicated intracellularly expressed genes are plotted on the y axis (log2 reads). P values were calculated using Student’s t test. (D) Box plots showing the effects of in vitro siRNA knockdown of PCSK9 in keratinocyte cell lines on IL36B and IL36G. PCSK9 (positive control) and PGK1 (negative control) expression is also shown for scrambled siRNA transfected and PCSK9 siRNA transfected cultures. Each dot represents an independently cultured and independently transfected HaCaT keratinocyte cell line (n = 3). P values were calculated with Student’s t test.

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