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

Journal of Translational Autoimmunity

Adolfo Flores-Saiffe Farías, M. Sc.¹  Rocío del Carmen Chávez Álvarez, Ph. D.²  Andrea Virginia Ruiz Ramírez, M. Sc.²  Ernesto Prado Montes de Oca, M.Sc., Ph.D.² 

[1] Doctorate Program in Human Genetics, Health Sciences Campus (CUCS), Guadalajara University, Sierra Mojada 950, Col. Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico;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;

关键词: Psoriasis;    Bioinformatics;    Gene expression regulation;    Single nucleotide polymorphism;    Regulatory SNPs;    Transcription factors;   

DOI  :  

来源: DOAJ

【 摘 要 】

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), TH1 and TH17 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).

【 授权许可】

Unknown