Functional characterization of genetic variants associated with response to tumor necrosis factor inhibitors in psoriatic arthritis patients.

Abstract

Psoriatic arthritis is a chronic, progressive inflammatory disease associated with psoriasis, affecting joints, entheses, and the axial skeleton. Treatment options have evolved from broad immunosuppressive therapies to targeted biologic agents. These therapies are generally safe and effective, but patient response varies considerably, emphasizing the importance of pharmacogenetic studies in the identification of variants that predict treatment response. This review explores the potential functional significance and causality of variants that were associated with response to tumor necrosis factor inhibitors by assessing their regulatory impact on gene expression, alternative splicing, transcription factor binding, chromatin state, and chromatin accessibility, using a combination of in silico resources. This integrated analysis revealed novel regulatory roles for specific variants. The variants rs1801274 in FCGR2A and rs396991 in FCGR3A have established biological roles in inflammation. The risk allele of variant rs767455 in TNFRSF1A correlates with increased TNFRSF1A expression and favors the splicing event that generates a TNFRSF1A soluble isoform lacking exon 6, resulting in increased inflammation. The variant rs20575 within TNFRSF10A correlates with the expression of the nearby inflammatory TNFRSF10D gene. The TNF variant rs1800610 correlates with changes in the expression of many nearby genes of the Human Leukocyte Antigen region. The variant rs610604, located within TNFAIP3, correlates with changes in the expression and splicing isoforms of WAKMAR2, a lncRNA with an anti-inflammatory role. In conclusion, the majority of variants associated with treatment response show strong evidence of a potential role in inflammation and psoriatic arthritis and may serve as clinical biomarkers pending replication and functional validation.