Genetically determined physiologically increased levels of interleukin (IL)-17 are associated with a lower risk for psoriatic arthritis (PsA), according to study findings published in Rheumatology.
The objective of the current Mendelian randomization study was to explore the effect of genetically predicted tumor necrosis factor (TNF)-α, IL-12p70, and IL-17 levels on risk for PsA.
Using genome-wide association studies, loci influencing normal physiologic levels of TNF- α, IL-12p70, and IL-17 were identified in 8293 healthy Finnish individuals from 3 independent population cohorts, as exposure. A genome-wide association study for PsA from the United Kingdom Biobank, including 900 patients with PsA and 462,033 control participants, was used as the outcome.
In total, there were 11 harmonized single-nucleotide variants (SNVs; formerly single-nucleotide polymorphisms [SNPs]) of TNF-α, 21 SNVs of IL-12p70, and 17 SNVs of IL-17 for PsA. Of the 17 SNVs for PsA, 7 were identified as instrumental SNVs that genetically determined increased IL-17 plasma concentrations and 5 as instrumental SNVs that genetically determined decreased levels.
Mendelian randomization analysis using the inverse-variance weighted method with 7 SNVs suggested that genetically determined increased IL-17 plasma concentrations were significantly associated with decreased risk for PsA (β=-0.00186 per allele; SE, 0.00043; P =.002). Analysis using the weighted median method was consistent and suggested a weak causal association between increased IL-17 levels and decreased risk for PsA (β=-0.00145 per allele; SE, 0.00059; P =.014). However, the MR-Egger analysis reported a nonsignificant association (β=0.00133 per allele; SE, 0.00087; P =.087).
While results of the SNV Mendelian randomization analysis may support a potential causal association between increased IL-17 levels and PsA risk, the researchers did not observe a causal association between genetically predicted reduced IL-17 levels and PsA risk, using the inverse-variance, MR-Egger, or weighted median methods. Overall, no association was found for genetically predicted increased and reduced TNF-α and IL-12p70 levels and risk for PsA in all 3 statistical methods.
The assumed linear association between exposure and outcome in the standard Mendelian randomization is one of the main limitations of the study. Additional limitations included differences between populations from Finland and the UK in depletion or enrichment of rare variants and protein-coding genetic variation, and the limited sensitivity of the genomic-wide association study to identify the causative mutation.
“Our findings provide preliminary evidence that genetic variants predisposing to a higher physiological IL-17 level are associated with a decreased risk [for] PsA,” the researchers concluded.
Wu D, Wong P, Lam SHM, et al. The causal effect of interleukin-17 on the risk of psoriatic arthritis: a Mendelian randomization study. Rheumatology (Oxford). Published online November 2020. doi:10.1093/rheumatology/keaa629