. 2021 Apr 5:4:100096.

doi: 10.1016/j.jtauto.2021.100096. eCollection 2021.

Predicted regulatory SNPs reveal potential drug targets and novel companion diagnostics in psoriasis

Andrea Virginia Ruiz Ramírez^{1

2}, Adolfo Flores-Saiffe Farías¹, Rocío Del Carmen Chávez Álvarez¹, Ernesto Prado Montes de Oca^{1

3

4

5}

Affiliations

¹ Laboratory of Regulatory SNPs, Personalized Medicine National Laboratory (LAMPER), Medical and Pharmaceutical Biotechnology, Research Center of Technology and Design Assistance of Jalisco State (CIATEJ A.C.), National Council of Science and Technology (CONACYT), C.P. 44270, Guadalajara, Jalisco, Mexico.
² Doctorate Program in Human Genetics, Health Sciences Campus (CUCS), Guadalajara University, Sierra Mojada 950, Col. Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico.
³ Laboratory of Pharmacogenomics and Preventive Medicine, LAMPER, Pharmaceutical and Medical Biotechnology, CIATEJ, A.C., CONACYT, C.P. 44270, Guadalajara, Jalisco, Mexico.
⁴ Scripps Research Translational Institute, 3344 North Torrey Pines Court, Suite 300, La Jolla, CA, 92037, USA.
⁵ Integrative Structural and Computational Biology, Scripps Research Institute, 10550 North Torrey Pines Road, SGM 300, La Jolla, CA, 92037, USA.

PMID: 33898962
PMCID: PMC8060581
DOI: 10.1016/j.jtauto.2021.100096

Predicted regulatory SNPs reveal potential drug targets and novel companion diagnostics in psoriasis

Andrea Virginia Ruiz Ramírez et al. J Transl Autoimmun. 2021.

. 2021 Apr 5:4:100096.

doi: 10.1016/j.jtauto.2021.100096. eCollection 2021.

Authors

Andrea Virginia Ruiz Ramírez^{1

2}, Adolfo Flores-Saiffe Farías¹, Rocío Del Carmen Chávez Álvarez¹, Ernesto Prado Montes de Oca^{1

3

4

5}

Affiliations

¹ Laboratory of Regulatory SNPs, Personalized Medicine National Laboratory (LAMPER), Medical and Pharmaceutical Biotechnology, Research Center of Technology and Design Assistance of Jalisco State (CIATEJ A.C.), National Council of Science and Technology (CONACYT), C.P. 44270, Guadalajara, Jalisco, Mexico.
² Doctorate Program in Human Genetics, Health Sciences Campus (CUCS), Guadalajara University, Sierra Mojada 950, Col. Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico.
³ Laboratory of Pharmacogenomics and Preventive Medicine, LAMPER, Pharmaceutical and Medical Biotechnology, CIATEJ, A.C., CONACYT, C.P. 44270, Guadalajara, Jalisco, Mexico.
⁴ Scripps Research Translational Institute, 3344 North Torrey Pines Court, Suite 300, La Jolla, CA, 92037, USA.
⁵ Integrative Structural and Computational Biology, Scripps Research Institute, 10550 North Torrey Pines Road, SGM 300, La Jolla, CA, 92037, USA.

PMID: 33898962
PMCID: PMC8060581
DOI: 10.1016/j.jtauto.2021.100096

Abstract

Psoriasis is an autoimmune disease associated with interleukins, their receptors, key transcription factors and more recently, antimicrobial peptides (AMPs). Cathelicidin LL-37 is an AMP proposed to play a fundamental role in psoriasis etiology. With our proprietary software SNPClinic v.1.0, we analyzed 203 common SNPs (MAF frequency > 1%) in proximal promoters of 22 genes associated with psoriasis. These include nine genes which protein products are classic drug targets for psoriasis (TNF, IL17A, IL17B, IL17C, IL17F, IL17RA, IL12A, IL12B and IL23A). SNPClinic predictions were run with DNAseI-HUP chromatin accessibility data in eight psoriasis/epithelia-relevant cell lines from ENCODE including keratinocytes (NHEK), T_H1 and T_H17 lymphocytes. Results were ranked quantitatively by transcriptional relevance according to our novel Functional Impact Factor (FIF) parameter. We found six rSNPs in five genes (CAMP/cathelicidin, S100A7/psoriasin, IL17C, IL17RA and TNF) and each was confirmed as true rSNP in at least one public eQTL database including GTEx portal and ENCODE (Phase 3). Predicted regulatory SNPs in cathelicidin, IL17C and IL17RA genes may explain hyperproliferation of keratinocytes. Predicted rSNPs in psoriasin, IL17C and cathelicidin may contribute to activation and polarization of lymphocytes. Predicted rSNPs in TNF gene are concordant with the epithelium-mesenchymal transition. In spite that these results must be validated in vitro and in vivo with a functional genomics approach, we propose FOXP2, RUNX2, NR2F1, ELF1 and HESX1 transcription factors (those with the highest FIF on each gene) as novel drug targets for psoriasis. Furthermore, four out of six rSNPs uncovered by SNPClinic v.1.0 software, could also be validated in the clinic as companion diagnostics/pharmacogenetics assays for psoriasis prescribed drugs that block TNF-α (e.g. Etanercept), IL-17 (e.g. Secukinumab) and IL-17 receptor (Brodalumab).

Keywords: Antimicrobial cationic peptides; Bioinformatics; Brodalumab; Cathelicidin; Etanercept; Gene expression regulation; Interleukin-17; Psoriasis; Regulatory SNPs; Secukinumab; Single nucleotide polymorphism; Transcription factors; Tumor necrosis factor.

PubMed Disclaimer

Conflict of interest statement

EPM has a granted patent for a small molecule that inhibits CAMP gene (cathelicidin LL-37) transcription.

Figures

**Fig. 1**
Proposed impact of the SNPClinic-predicted rSNPs in psoriasis (“ALL” population from 1000 Genomes Project). Figure was designed in Biorender by AVRR (https://biorender.com/)

**Fig. 2**
Genomic and epigenomic context (gene expression and histone markers as inputs of SNPClinic v.1.0) of rSNP rs9844566 (yellow vertical line) in proximal promoter of *CAMP* gene (cathelicidin LL-37). Figure generated at UCSC Genome Browser visual tool. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

**Fig. 3**
Violin plots of relative gene expression impacted by rs9844566 eQTL of *CAMP* gene (Chr.3) in not sun-exposed suprapubic skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 4**
Violin plots of relative gene expression impacted by rs9844566 eQTL of *CAMP* gene (Chr.3) in Skin - Sun Exposed [Lower leg] (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 5**
Violin plots of relative gene expression impacted by rs9844566 eQTL of *CAMP* gene (Chr.3) in Cells_EBV-transformed_lymphocytes (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 6**
Violin plots of relative gene expression impacted by rs9844566 eQTL of *CAMP* gene (Chr.3) in Whole_Blood (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 7**
Violin plots of relative gene expression impacted by rs9844566 eQTL of *CAMP* gene (Chr.3) in Brain_Cortex (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 8**
Violin plots of relative gene expression impacted by rs9844566 eQTL of *CAMP* gene (Chr.3) in Colon_Transverse (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 9**
Violin plots of relative gene expression impacted by rs11646542 eQTL of *IL17C* gene (Chr.16) in Not_Sun_Exposed_Suprapubic skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 10**
Violin plots of relative gene expression impacted by rs11646542 eQTL of *IL17C* gene (Chr.16) in Sun-Exposed Lower leg skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 11**
Violin plots of relative gene expression impacted by rs11646542 eQTL of *IL17C* gene (Chr.16) in Cells_EBV-transformed_lymphocytes (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 12**
Violin plots of relative gene expression impacted by rs11646542 eQTL of *IL17C* gene (Chr.16) in Whole_Blood (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 13**
Violin plots of relative gene expression impacted by rs4819958 eQTL of *IL1*7RA gene (Chr.22) in Not Sun-Exposed Suprapubic skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 14**
Violin plots of relative gene expression impacted by rs4819958 eQTL of *IL1*7RA gene (Chr.22) in Sun_-Exposed Lower leg skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 15**
Violin plots of relative gene expression impacted by rs4819958 eQTL of *IL1*7RA gene (Chr.22) in Cells_EBV-transformed_lymphocytes (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 16**
Violin plots of relative gene expression impacted by rs4819958 eQTL of *IL1*7RA gene (Chr.22) in Whole Blood (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 17**
Violin plots of relative gene expression impacted by rs4819958 eQTL of *IL1*7RA gene (Chr.22) in Brain_Cortex (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 18**
Violin plots of relative gene expression impacted by rs4819958 eQTL of *IL1*7RA gene (Chr.22) in Colon_Transverse (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 19**
Violin plots of relative gene expression impacted by rs361525 eQTL of *TNF* gene (Chr.6) in Not Sun-Exposed Suprapubic skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 20**
Violin plots of relative gene expression impacted by rs361525 eQTL of *TNF* gene (Chr.6) in Sun-Exposed Lower leg skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 21**
Violin plots of relative gene expression impacted by rs361525 eQTL of *TNF* gene (Chr.6) in Cells_EBV-transformed_lymphocytes (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 22**
Violin plots of relative gene expression impacted by rs361525 eQTL of *TNF* gene (Chr.6) in Whole_Blood (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 23**
Violin plots of relative gene expression impacted by rs361525 eQTL of *TNF* gene (Chr.6) in Brain_Cortex (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 24**
Violin plots of relative gene expression impacted by rs361525 eQTL of *TNF* gene (Chr.6) in Colon-Transverse (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 25**
Violin plots of relative gene expression impacted by rs1800629 eQTL of *TNF* gene (Chr.6) in Not Sun-Exposed Suprapubic skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 26**
Violin plots of relative gene expression impacted by rs1800629 eQTL of *TNF* gene (Chr.6) inSun-Exposed Lowerleg skin (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 27**
Violin plots of relative gene expression impacted by rs1800629 eQTL of TNF gene (Chr.6) in brain cortex (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 28**
Violin plots of relative gene expression impacted by rs1800629 eQTL of *TNF* gene (Chr.6) in Whole_Blood (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

**Fig. 29**
Violin plots of relative gene expression impacted by rs1800629 eQTL of *TNF* gene (Chr.6) in Colon_Transverse (GTEx portal). White bar= median. Numbers in x-axis indicate number of individuals.

See this image and copyright information in PMC

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Predicted regulatory SNPs reveal potential drug targets and novel companion diagnostics in psoriasis

Affiliations

Predicted regulatory SNPs reveal potential drug targets and novel companion diagnostics in psoriasis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References