Departamento Dermatología, Hospital Alvarez Buylla, Mieres, Spain.
Departamento Dermatología, Hospital Universitario Central Asturias, Oviedo, Spain.
Mol Diagn Ther. 2019 Oct;23(5):627-633. doi: 10.1007/s40291-019-00409-x.
Nuclear factor (NF)-κB is an essential mediator of the tumor necrosis factor (TNF) pathway, and has been implicated in psoriasis. NFKBIZ is a nuclear inhibitor of NF-κB with a prominent role in the pathogenesis of psoriasis. The genetic variation at the NFKBIZ gene has been associated with the risk of developing psoriasis, and could also contribute to defining the response to anti-TNF biological drugs.
The objectives of this study were to determine the association of a common NFKBIZ insertion/deletion (indel) polymorphism (rs3217713) with the response to adalimumab and determine the differences in the relative expression of a NFKBIZ alternative transcript in patients with a positive versus negative response.
We genotyped a common NFKBIZ polymorphism in 169 psoriasis patients treated with adalimumab classified as responders (n = 120) and non-responders (n = 49), according to whether they had a 75% reduction in the Psoriasis Area and Severity Index score (PASI75) at week 24. The Cw6 polymorphism was also determined and allele and genotype frequencies were compared between the groups. We also determined the rate of the expression of a NFKBIZ transcript lacking exon 10 relative to the normal transcript in 60 patients (27 non-responders). In addition, because the intron indel could affect RNA splicing, we investigated whether the level of the alternative transcript was related to the intronic genotype.
The NFKBIZ polymorphism was associated with adalimumab response, with carriers of the deletion allele significantly more frequent among responders (odds ratio = 2.76, 95% confidence interval 1.19-6.43; p = 0.015). The presence of the HLA-CW6 allele was also associated with a positive response in our cohort (p = 0.018). The alternative transcript was amplified in all the samples. We found higher but non-significant values of normal to alternative transcript in responders as well as in NFKBIZ insertion homozygotes.
Our study supported a significant effect of a common NFKBIZ polymorphism on the response to adalimumab. This result could help to optimize the prescription of this anti-TNF, but requires confirmation in other cohorts.
核因子（NF）-κB 是肿瘤坏死因子（TNF）途径的重要介质，与银屑病有关。NFKBIZ 是 NF-κB 的核抑制剂，在银屑病的发病机制中起重要作用。NFKBIZ 基因的遗传变异与患银屑病的风险有关，也可能有助于确定对 TNF 生物药物的反应。
本研究的目的是确定常见的 NFKBIZ 插入/缺失（indel）多态性（rs3217713）与阿达木单抗治疗反应的相关性，并确定阳性和阴性反应患者中 NFKBIZ 替代转录本的相对表达差异。
我们对 169 名接受阿达木单抗治疗的银屑病患者进行了 NFKBIZ 常见多态性基因分型，根据他们在第 24 周时是否达到银屑病面积和严重程度指数（PASI75）评分下降 75%，将患者分为应答者（n=120）和无应答者（n=49）。还确定了 Cw6 多态性，并比较了两组之间的等位基因和基因型频率。我们还在 60 名患者（27 名无应答者）中确定了缺乏外显子 10 的 NFKBIZ 转录本与正常转录本的表达率。此外，由于内含子 indel 可能影响 RNA 剪接，我们研究了替代转录本的水平是否与内含子基因型有关。
NFKBIZ 多态性与阿达木单抗治疗反应相关，缺失等位基因携带者在应答者中更为常见（比值比=2.76，95%置信区间 1.19-6.43；p=0.015）。我们的队列中 HLA-CW6 等位基因的存在也与阳性反应相关（p=0.018）。所有样本均扩增了替代转录本。我们发现应答者和 NFKBIZ 插入纯合子的正常到替代转录本的比值较高，但无统计学意义。
我们的研究支持常见 NFKBIZ 多态性对阿达木单抗治疗反应的显著影响。这一结果有助于优化该抗 TNF 的处方，但需要在其他队列中得到证实。
