Kim Hyun Jeong, Trinh Nga Thi, Choi Yunjeong, Kim Woorim, Min Kyung Hyun, Kang Sang Oh, Kim Joo Hee, Kim Hyoun-Ah, Jung Ju-Yang, Choi In Ah, Lee Kyung Eun
College of Pharmacy, Chungbuk National University, Cheongju-si, Republic of Korea.
College of Pharmacy, Ajou University, Suwon, Republic of Korea.
Pharmgenomics Pers Med. 2020 Mar 16;13:81-88. doi: 10.2147/PGPM.S235035. eCollection 2020.
TNF-α is a transmembrane protein which requires cleavage by ADAM17 in order to act systemically. The activation of ADAM17 to generate soluble TNF‑α results in an increased inflammatory activity. We hypothesized that variants spanning the ADAM17 gene contribute towards the observed variation in patient response defined by the number of changes in TNF‑α inhibitors.
Seven single-nucleotide polymorphisms (SNPs) of ADAM17 in 63 patients with rheumatoid arthritis who received TNF-α inhibitors were analyzed: rs57467365, rs62117540, rs117645314, rs6432013, rs532704607, rs117179141, and rs12692386. Univariate and multivariate regression analysis were employed to investigate the independent predictable factors for changes in TNF-α inhibitors.
ADAM17 rs117645314 and rs117179141 showed significant association with the number of changes in TNF-α inhibitors. Patients with GA in rs117645314 and AT in rs117179141 had significantly higher chance of two or more changes of TNF-α inhibitors than those with wild homozygous alleles. Multivariate analysis showed that rs117179141 explained 5.7% of the 23.8% variability in TNF-α inhibitor response.
This study showed that the number of changes in TNF-α inhibitor is associated with ADAM17 SNPs.
肿瘤坏死因子-α（TNF-α）是一种跨膜蛋白，需要经ADAM17裂解才能发挥全身作用。ADAM17激活产生可溶性TNF-α会导致炎症活性增加。我们推测，ADAM17基因上的变异会导致患者对TNF-α抑制剂反应的变化，而这种变化可以通过TNF-α抑制剂的更换次数来体现。
对63例接受TNF-α抑制剂治疗的类风湿关节炎患者的ADAM17基因的7个单核苷酸多态性（SNP）进行分析：rs57467365、rs62117540、rs117645314、rs6432013、rs532704607、rs117179141和rs12692386。采用单因素和多因素回归分析来研究TNF-α抑制剂更换的独立预测因素。
ADAM17基因的rs117645314和rs117179141与TNF-α抑制剂的更换次数显著相关。rs117645314基因型为GA以及rs117179141基因型为AT的患者，其TNF-α抑制剂更换两次或更多次的可能性显著高于野生纯合等位基因的患者。多因素分析显示，rs117179141可以解释TNF-α抑制剂反应中23.8%变异性中的5.7%。
本研究表明，TNF-α抑制剂的更换次数与ADAM17基因的单核苷酸多态性有关。
