Background/Purpose: Biologic agents targeting cytokines including TNF-α, IL-12p70 and IL-17 have been proven to be very effective in treating psoriatic arthritis (PsA).  Nonetheless, whether these cytokines are causally associated with PsA is uncertain. The study aims to compare causal associations between genetically predicted cytokine level and risk of psoriatic arthritis via a two-sample Mendelian Randomization approach.

Methods: We used the publicly available summary-level findings from genome-wide association studies (GWAS) for identification of loci influencing concentrations of circulating cytokines (PMID: 27989323, n=8 293) as exposure and a GWAS for non-cancer illness code self-reported: PsA from the individuals included in the UK Biobank (total n = 462 933; case = 900, control = 462 033) as the outcome. A two-sample Mendelian randomization (MR) analysis was performed using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. Sensitivity analysis and MR-Egger regression analysis were performed to evaluate the heterogeneity and pleiotropic effects of each variant.

Results: Single-nucleotide polymorphisms (SNPs) at genome-wide significance from GWASs on TNF-α (6 and 3 SNPs for increased and decreased TNF-α levels respectively), IL-12p70 (9 and 5 SNPs for increased and decreased in IL-12p70 levels respectively), IL-17 (7 and 5 SNPs for increased and decreased IL-17 levels respectively) were identified as the instrumental variables (IVs).    Our results provided evidence to support a causal association between elevated level of Il-17 (IVs: rs117556572, rs141312283, rs149738638, rs17282552, rs187475560, rs57920188, rs62191444) and PsA (MR Egger, p = 0.087; Weighted median: p=0.014; Inverse variance weighted: p= 0.002).  All three methods did not show any causal association between PsA and increased and decreased TNF-α and IL-12p70, and decreased IL-17 level (Table 1).  Cochran’s Q test and the funnel plot indicated no evidence of heterogeneity and asymmetry, indicating no directional pleiotropy.

Conclusion: Our findings provided strong evidence on the causal association of genetically elevated circulating IL-17 levels with the risk of developing psoriatic arthritis. IL-17 blockade might prevent the transition from psoriasis to psoriatic arthritis that warrants testing in suitably powered randomized trials.

Abstract_ACR 2019_table

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/causal-effect-of-tnf-%ce%b1-il-12p70-il-17-levels-on-the-risk-of-psoriatic-arthritis-a-mendelian-randomization-study/