Ren Yunqing, Wang Ling, Dai Huatuo, Qiu Guiying, Liu Jipeng, Yu Dianhe, Liu Jianjun, Lyu Cheng-Zhi, Liu Lunfei, Zheng Min
Department of Dermatology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
Department of Dermatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Front Pharmacol. 2022 Aug 19;13:968935. doi: 10.3389/fphar.2022.968935. eCollection 2022.
TNF-α inhibitors are effective biological agents for treating psoriasis, but the treatment responses differ across patients. This study aimed to identify genetic biomarkers of anti-TNF-α response in Chinese psoriasis patients using a genome-wide association approach. We recruited two independent cohorts of Chinese psoriasis patients administered etanercept biosimilar (with or without methotrexate). We identified 61 and 87 good responders (PASI improvement ≥75%), 19 and 10 poor responders (PASI improvement <50%) after 24 weeks treatment in the two cohorts, respectively. Then we performed genome-wide association studies (GWAS) on anti-TNF-α response in each cohort independently, followed by a fixed-effects inverse-variance meta-analysis in the 148 good and 29 poor responders. We tested genetic associations with >3 million genetic variants in either cohort. Meta-analysis identified significant associations within seven loci at < 10, which also showed consistent association evidence in the two cohorts. These seven loci include rs2431355 (OR = 6.65, = 4.46 × 10, on 5q13.3), rs11801616 (OR = 0.11, = 1.75 × 10, on 1p35.2), rs3754679 (OR = 0.17, = 7.71 × 10, on 2q11.2), rs13166823 (OR = 0.09, = 3.71 × 10, on 5q31.1), rs10220768 (OR = 5.49, = 1.48 × 10, on 15q11.2), rs4796752 (OR = 5.56, = 1.49 × 10, on 17q21.2), and rs13045590 (OR = 0.08, = 9.67 × 10, on 20q13.3). Of the seven SNPs, six SNPs showed significant eQTL effect ( < 1 × 10) for several genes in multiple tissues. These results suggest novel biological mechanisms and potential biomarkers for the response to anti-TNF therapies. These findings warrant further validation.
肿瘤坏死因子-α（TNF-α）抑制剂是治疗银屑病的有效生物制剂，但不同患者的治疗反应存在差异。本研究旨在采用全基因组关联方法，在中国银屑病患者中鉴定抗TNF-α反应的遗传生物标志物。我们招募了两个独立队列的中国银屑病患者，给予依那西普生物类似药（联合或不联合甲氨蝶呤）治疗。在两个队列中，分别有61例和87例治疗24周后达到良好反应者（银屑病面积和严重程度指数[PASI]改善≥75%），19例和10例治疗反应不佳者（PASI改善<50%）。然后我们在每个队列中独立开展抗TNF-α反应的全基因组关联研究（GWAS），随后在148例良好反应者和29例不佳反应者中进行固定效应逆方差荟萃分析。我们在任一队列中检测了与超过300万个遗传变异的遗传关联。荟萃分析在<10−8水平鉴定出7个位点存在显著关联，在两个队列中也显示出一致的关联证据。这7个位点包括rs2431355（比值比[OR]=6.65，P=4.46×10−10，位于5q13.3）、rs11801616（OR=0.11，P=1.75×10−9，位于1p35.2）、rs3754679（OR=0.17，P=7.71×10−9，位于2q11.2）、rs13166823（OR=0.09，P=3.71×10−9，位于5q31.1）、rs10220768（OR=5.49，P=1.48×10−8，位于15q11.2）、rs4796752（OR=5.56，P=1.49×10−8，位于17q21.2）和rs13045590（OR=0.08，P=9.67×10−9，位于20q13.3）。在这7个单核苷酸多态性（SNP）中，6个SNP在多个组织中对多个基因显示出显著的表达数量性状位点（eQTL）效应（P<1×10−5）。这些结果提示了抗TNF治疗反应的新生物学机制和潜在生物标志物。这些发现有待进一步验证。
