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NFKBIZ and CW6 in Adalimumab Response Among Psoriasis Patients: Genetic Association and Alternative Transcript Analysis

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Abstract

Background

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.

Objectives

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgements

This work was supported by grant PI16/01792 from the Spanish Plan Nacional de I+D+I Ministerio de Economía y Competitividad and the European FEDER. We thank the personnel of the Laboratory Department of CHU-Pontevedra for helping in the recruitment of the patients.

Author information

Authors and Affiliations

  1. Departamento Dermatología, Hospital Alvarez Buylla, Mieres, Spain

    Pablo Coto-Segura

  2. Departamento Dermatología, Hospital Universitario Central Asturias, Oviedo, Spain

    Leire González-Lara

  3. Genética Molecular, Hospital Universitario Central Asturias, 33011, Oviedo, Spain

    Eliecer Coto

  4. Departamento Reumatología, Hospital Universitario Central Asturias, Oviedo, Spain

    Rubén Queiro

  5. Servicio de Dermatología, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain

    Ana Batalla

  6. Complejo Hospitalario Universitario de León, León, Spain

    Noemí Eiris

  7. Instituto Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain

    Eliecer Coto

  8. Departamento Medicina, Universidad Oviedo, Oviedo, Spain

    Eliecer Coto

Authors
  1. Pablo Coto-Segura
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  2. Leire González-Lara
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  3. Ana Batalla
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  4. Noemí Eiris
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  6. Eliecer Coto
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Corresponding author

Correspondence to Eliecer Coto.

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Conflict of interest

Pablo Coto-Segura, Leire González-Lara, Ana Batalla, Noemí Eiris, Rubén Queiro, and Eliecer Coto declare that they have no competing interests related to this work.

Funding

This work was supported by a grant from the Spanish Instituto de Salud Carlos III-European FEDER (European Regional Development) funds (Grant PI16/01792).

Author contributions

All authors contributed to this work by recruiting the cohort or performing the genetic and statistical analysis.

Data availability

A summary of the data on the patients included in the study is provided as a table in the Electronic Supplementary Material.

Electronic Supplementary Material

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Supplementary material 1 (DOC 858 kb)

Supplementary material 2 (DOC 297 kb)

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Coto-Segura, P., González-Lara, L., Batalla, A. et al. NFKBIZ and CW6 in Adalimumab Response Among Psoriasis Patients: Genetic Association and Alternative Transcript Analysis. Mol Diagn Ther 23, 627–633 (2019). https://doi.org/10.1007/s40291-019-00409-x

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  • DOI: https://doi.org/10.1007/s40291-019-00409-x

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