Pharmacogenomics-Based Detection of Variants Involved in Pain, Anti-inflammatory and Immunomodulating Agents Pathways by Whole Exome Sequencing and Deep in Silico Investigations Revealed Novel Chemical Carcinogenesis and Cancer Risks

TL;DR

This study uses whole exome sequencing and in silico analysis to identify genetic variants linked to pain and drug response pathways, revealing new cancer risks.

Contribution

The study introduces a pharmacogenomics panel for Pain, Anti-inflammatory, and Immunomodulating agents pathways and identifies novel cancer risks.

Findings

Identified 54 genetic variants in Iranians related to drug response pathways.

Six actionable variants showed significant deviations from the reference genome.

Protein and gene interactions suggest potential cancer risks from these pathways.

Abstract

Next-Generation Sequencing (NGS) methods specifically Whole-Exome Sequencing (WES) have demonstrated promising findings with a high accuracy of 91%-99% in Pharmacogenomics (PGx). A PGx-based panel can be utilized to minimize adverse drug reactions (ADRs) and maximize the treatment efficacy. Remarkably, Cancer Pain Management (CPM) is a cutting-edge concept in modern medicine. Thus, this study aimed to investigate the WES results by a PGx-based panel containing genes involved in Pain, Anti-inflammatory, and Immunomodulating agents (PAIma) signaling pathways.

A total of 200 unrelated Iranians (100 western and 100 northern) were included. 100 WES results were analyzed through the PAIma panel. After DNA extraction, 100 samples were genotyped by Multiplex-Amplification-Refractory Mutation System (ARMS) PCR.
A primary in silico investigation performed on 128 candidate genes through Protein-Protein Interactions (PPIs) and Gene-miRNA Interactions (GMIs) via the STRING database, and miRTargetLink2, respectively. Additionally, Enrichment Analysis (EA) was applied to find the unknown interplays among these three major pathways by Enrichr.

55,590 annotations through 21 curated pathways were filtered, 900 variants were found, and 128 genes were refined. Finally, 54 candidate variants (48 non-synonymous single nucleotide variants (nsSNVs), 2 stop-gained, 1 frameshift, and 3 splicing) remained.

Conclusively, six potentially actionable variants including rs1695 (GSTP1), rs628031 (SLC22A1), rs17863778 (UGT1A7),
rs16947 (CYP2D6), rs2257401 (CYP3A7), and rs2515641 (CYP2E1) had the most deviations among Iranians, compared with the reference genome, which should be genotyped for drug prescribing. Remarkably, PPIs, GMIs, and EA revealed potential risks of carcinogenesis and cancer phenotypes resulting from PAIma pathways genes.

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