Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling

Background Multiple treatment options are available for the management of psoriasis, but clinical response varies among individual patients and no biomarkers are available to facilitate treatment selection for improved patient outcomes.Objectives To utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis.Methods We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1942 genotyped patients with psoriasis. We examined 6 502 658 genetic markers to model their associations with response to six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomics, transcriptomics and a longitudinal clinical cohort to provide biological implications for the topmost signals associated with drug response.Results Two novel markers were revealed to be associated with treatment response: rs1991820 (P = 1.30 x 10-6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P = 2.94 x 10-6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (P = 1.0 x 10-12) and CD200 (P = 5.4 x 10-6). We demonstrated that KLK7 expression was increased in the psoriatic epidermis, as shown by immunohistochemistry, as well as single-cell RNA sequencing, and its responsiveness to anti-TNF treatment was highlighted. By inhibiting the expression of KLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF.Conclusions Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7. We conducted a retrospective pharmacogenetic study using self-treatment evaluation from 1942 genotyped patients with psoriasis to model the genetic associations with responses from six psoriasis treatments. We revealed that an anti-tumour necrosis factor (TNF) response-associated variant (rs1991820) is also associated with KLK7 expression. Our study implicates the genetic regulation of cytokine responses in predicting clinical drug response and supports the association between pharmacogenetic loci and anti-TNF response, as shown here for KLK7.