Genetically proxied TYK2 inhibition is associated with reduced sarcoidosis susceptibility

Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology that can affect any organ, including the lung, joints and skin. Clinical presentation can be highly heterogeneous and lead to significant morbidity and mortality. Glucocorticoids remain the cornerstone of pharmacological therapy but are limited by toxicities with longterm use. Although steroidsparing agents are available, there are no licensed therapeutics for sarcoidosis. Many cytokines implicated in sarcoidosis (eg, gamma interferon and other type 1 cytokines) signal via the JAKSTAT pathway, and inhibition of this pathway has proved successful in several immunemediated inflammatory diseases (IMIDs). Interestingly, tofacitinib, a JAKSTAT inhibitor, was associated with skin improvement and suppression of type 1 cytokines in an openlabel trial of 10 patients with cutaneous sarcoidosis. However, these preliminary findings await confirmation by phase III trials and are caveated by tofacitinib’s potential adverse cardiovascular profile. Inhibition of TYK2, one member of the JAK family, has shown promise for IMIDs (eg, deucravcitinib for psoriasis and psoriatic arthritis (PsA)). Germline mutations causing lossoffunction of genes encoding drug targets have been used to correctly predict the effect of their pharmacological inhibition; therefore, we used a naturally occurring lossoffunction mutation to evaluate the therapeutic potential of TYK2i for sarcoidosis. The rs34536443 (P1104A) variant has a minor allele frequency of ~4% in European populations. Homozygosity of the minor allele causes nearcomplete loss of TYK2 function and consequently impairs type 1 cytokine signalling, while heterozygosity reduces function by ~40%. We used data from the UK Biobank (UKB), a cohort study of ~0.5 million participants 37–73 years of age. The rs34536443 minor allele was regressed against 1012 sarcoidosis cases (defined by International Classification of Diseases (ICD) and primary care codes) and 5450 randomly selected controls of selfreported White British ancestry. Analysis was adjusted for the first 10 principal components. Results were replicated using publicly available data from the FinnGen study (Release 7; 3103 cases, 304 494 controls). To validate rs34536443 as a proxy for TYK2i, we examined its effect on risk of psoriasis and PsA as positive controls using published genetic association data. Chronic widespread musculoskeletal pain was used as a negative control. Detailed methods, including case definition and references for each GWAS, are provided in online supplemental materials. Where possible, estimates for each disease were pooled using fixedeffect metaanalysis. Each additional minor allele of rs34536443 was associated with reduced sarcoidosis susceptibility in both UKB and FinGenn data (figure 1), with pooled OR 0.62 (95% CI 0.54 to 0.71; p=2.38×10). rs34536443 was also associated with psoriasis (OR 0.65; 95% CI 0.60 to 0.70; p=1.59×10) and PsA (OR 0.65; 95% CI 0.57 to 0.74; p=1.83×10), but not chronic widespread pain. Using large population level genetic data, we showed consistent associations between a lossoffunction TYK2 mutation and sarcoidosis, which supports the use of TYK2i for reducing sarcoidosis susceptibility. Several limitations should be recognised: First, the risk variants for disease incidence do not always coincide with disease progression. Second, estimates derived using the lossoffunction variant that reflects a lifelong exposure may not reflect shorter durations of pharmacological intervention. Similar point estimates observed for sarcoidosis and psoriatic disease may not predict equivalent efficacy for future sarcoidosis trials, since upstream cytokines transduced through TYK2 are likely to differ across these diseases. Placebo controlled clinical trials are needed to examine the therapeutic effect of TYK2i in established sarcoidosis. However, similar findings for the lossoffunction variant and susceptibility of other IMIDs, for which the predicted efficacy of TYK2i is established, support it as a potential therapeutic target. Third, case misclassification is possible when using coded data to define sarcoidosis; however, this is likely to reduce power and bias towards the null, as can be see when comparing estimates between physician diagnosed and ICDderived psoriasis. Lastly, studies in other populations, particularly those of African ancestry in whom sarcoidosis is more prevalent, are needed to confirm generalisability of our findings. In summary, genetically proxied TYK2i is associated with reduced sarcoidosis susceptibility, which may support drug development programmes for its management.