Predicted regulatory SNPs reveal potential drug targets and novel companion diagnostics in psoriasis.
Ruiz Ramírez. Andrea Virginia AV; Flores-Saiffe Farías. Adolfo A; Chávez Álvarez. Rocío Del Carmen RDC; Prado Montes de Oca. Ernesto E
Key Findings
- Six regulatory SNPs were identified in five psoriasis‑related genes, including the LL‑37 gene (CAMP).
- These SNPs were supported by eQTL data from GTEx and ENCODE, indicating they affect gene expression.
- Transcription factors FOXP2, RUNX2, NR2F1, ELF1, and HESX1 were highlighted as potential new drug targets.
- Four of the six SNPs could serve as companion diagnostics for biologic drugs that block TNF‑α or IL‑17 pathways.
Practical Outcomes
- For biohackers, the main takeaway is that genetic testing for the highlighted SNPs might help predict psoriasis risk and response to certain biologic therapies. While the findings don’t change how to use LL‑37 directly, they point to future personalized approaches and new drug targets that could eventually influence treatment strategies.
Summary
Researchers used a computer tool to find DNA variants near the gene that makes the antimicrobial peptide LL‑37 and other psoriasis‑related genes. Six variants looked like they could change how much of these proteins are made, and some of them match data from public gene‑expression databases. The study suggests new drug targets and possible genetic tests to predict who will respond to existing psoriasis medicines.
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 (<i>TNF, IL17A, IL17B, IL17C, IL17F, IL1</i>7RA<i>, IL12A, IL12B</i> and <i>IL23A</i>). SNPClinic predictions were run with DNAseI-HUP chromatin accessibility data in eight psoriasis/epithelia-relevant cell lines from ENCODE including keratinocytes (NHEK), T<sub>H</sub>1 and T<sub>H</sub>17 lymphocytes. Results were ranked quantitatively by transcriptional relevance according to our novel Functional Impact Factor (FIF) parameter. We found six rSNPs in five genes (<i>CAMP</i>/cathelicidin, <i>S100A7/</i>psoriasin<i>, IL17C, IL1</i>7RA and <i>TNF</i>) 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, <i>IL17C</i> and <i>IL1</i>7RA genes may explain hyperproliferation of keratinocytes. Predicted rSNPs in psoriasin, <i>IL17C</i> and cathelicidin may contribute to activation and polarization of lymphocytes. Predicted rSNPs in <i>TNF</i> gene are concordant with the epithelium-mesenchymal transition. In spite that these results must be validated <i>in vitro</i> and <i>in vivo</i> 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).
Study Information
pubmed
2021
2021-04-05T00:00:00.000Z
10.1016/j.jtauto.2021.100096
6
45