Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in TNF signaling

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.We aim to utilize retrospective data to conduct a pharmacogenetic study. This design can bypass the obstacle of patient follow-up in prospective study and increase the sample size. Successful implementation of the study can nominate new candidates and their target genes to explore the potential genetic pathways associated with drug response in the treatment of psoriasis.We conducted a retrospective pharmacogenetic study using self-evaluated treatment response from 1,942 genotyped psoriatic patients. We examined 6,502,658 genetic markers to model their associations with responses from six treatment options using linear regression, adjusting for cohort variables and demographic features. We further utilized an integrative approach incorporating epigenomic, transcriptomic, and a longitudinal clinical cohort to provide biological implications for the top signals associated with drug response.Two novel markers were revealed to be associated with treatment response: rs1991820 (p = 1.30×10-6) for anti-TNF biologics; and rs62264137 (p = 2.94×10-6) for methotrexate, which also associated with cutaneous mRNA expression levels of two known psoriasis-related genes KLK7 (p = 1.0×10-12) and CD200 (p = 5.4×10-6). We demonstrate that KLK7 expression is increased in the psoriatic epidermis as shown by immunohistochemistry as well as single-cell RNA-sequencing, and we highlight its responsiveness to anti-TNF treatment. By inhibiting the expression of KLK7, we further illustrate keratinocytes have decrease in pro-inflammatory responses to TNF.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.