Circulating metabolites mediating the effect of psoriatic arthritis on Crohn disease risk: A mediation Mendelian...

Psoriatic arthritis (PsA) and Crohn disease (CD) are chronic immune-mediated illnesses that afflict a growing number of adults and children worldwide. Observational studies have revealed a link between PsA and CD, but the modifiable risk variables that mediate the causal effects remain unknown. We aim to look into the relationship between PsA and CD, and to see if circulating metabolites have a role in the pathophysiology of both disorders. By scanning the whole genome of a large number of people and detecting millions of genetic variation sites in the genome, we take advantage of the random assignment of genotypes in nature and use single nucleotide polymorphisms as instrumental variables to simulate the environment of randomized controlled trials, so as to infer the causal relationship between exposure factors and outcomes. Using summary statistics from genome-wide association studies of predominantly European ancestry, we used two-sample Mendelian randomization (MR) to estimate the effects of PsA on CD (1637 cases/212,242 controls; 1401 cases/461,532 controls), and two-step MR to assess the association with 1400 circulating metabolites. Genetic predisposition to PsA was associated with a higher risk of CD (pooled odds ratio, 1.00051; 95% confidence interval [CI], 1.00023-1.00078; P < .001). The statistical association between PsA and CD was mediated by the concentrations of homocitrulline, 5-hydroxyhexanoate, carnitine C14, gamma-glutamylthreonine, furaneol sulfate, and trans-urocanate, which accounted for 4.23% (95% CI, -0.68% to 9.15%, P = 4.58 × 10-2), 7.85% (95% CI, -1.74% to 17.44%, P = 9.91 × 10-3), 6.09% (95% CI, -1.70% to 13.88%, P = 3.09 × 10-2), 7.45% (95% CI, -1.21% to 16.11%, P = 1.31 × 10-3), 8.88% (95% CI, 0.23% to 17.54%, P = 8.39 × 10-3), and 3.96% (95% CI, -0.48% to 8.40%, P = 2.29 × 10-2) of the total effect, respectively. Our MR analysis identified significant PsA-CD associations mediated through specific metabolites, particularly the gut microbiome-derived furaneol sulfate (showing highest mediation), supporting gut-joint axis involvement. These findings establish a crucial theoretical framework for guiding clinical practice in the management of PsA and CD.