Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling.
Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling.
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银屑病的回顾性药物遗传学研究强调了 KLK7 在肿瘤坏死因子信号传导中的作用。
DOI：
10.1093/bjd/ljad332
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发表时间：
2023
期刊：
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T
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作者：
Zhang,Haihan;Patrick,MatthewT;Tejasvi,Trilokraj;Sarkar,MrinalK;Wasikowski,Rachael;Stuart,PhilipE;Li,Qinmengge;Xing,Xianying;Voorhees,JohnJ;Ward,NicoleL;He,Kevin;Zhou,Xiang;Gudjonsson,JohannE;Nair,RajanP;Elder,JamesT;T
背景银屑病的治疗有多种选择，目的利用回顾性资料进行药物遗传学研究，探讨银屑病治疗中与药物反应相关的潜在遗传学途径。评价了1942例银屑病基因分型患者的治疗反应。我们检查了6502658个遗传标记，使用线性回归对其与六种治疗方案的反应进行建模，调整队列变量和人口统计学特征。我们进一步利用整合的方法，将表观基因组学，转录组学和纵向临床队列，以提供与药物反应相关的最高信号的生物学意义。（P = 1.30 × 10 - 6）抗肿瘤坏死因子（TNF）生物制剂;和rs62264137（P = 2.94 × 10 - 6）甲氨蝶呤，与银屑病相关基因KLK 7（P = 1.0 × 10 - 12）和CD 200（P = 5.4 × 10 - 6）的mRNA表达水平相关。免疫组化和单细胞RNA测序显示，我们证明银屑病表皮中KLK 7表达增加，并强调了其对抗TNF治疗的反应性。通过抑制ofKLK 7的表达，我们进一步说明，角质形成细胞有降低促炎反应TNF.ConclusionsOur研究牵连的细胞因子反应的遗传调控在预测临床药物反应，并支持药物遗传学位点和抗TNF反应之间的关联，如这里所示forKLK 7。
BackgroundMultiple 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.ObjectivesTo utilize retrospective data to conduct a pharmacogenetic study to explore the potential genetic pathways associated with drug response in the treatment of psoriasis.MethodsWe 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.ResultsTwo novel markers were revealed to be associated with treatment response: rs1991820 (P= 1.30 × 10–6) for anti-tumour necrosis factor (TNF) biologics; and rs62264137 (P= 2.94 × 10–6) for methotrexate, which was also associated with cutaneous mRNA expression levels of two known psoriasis-related genesKLK7(P= 1.0 × 10–12) andCD200(P= 5.4 × 10–6). We demonstrated thatKLK7expression 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 ofKLK7, we further illustrated that keratinocytes have decreased proinflammatory responses to TNF.ConclusionsOur 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 forKLK7.