Elsevier

Human Immunology

Volume 78, Issues 5–6, May–June 2017, Pages 435-440
Human Immunology

NFKBIZ in Psoriasis: Assessing the association with gene polymorphisms and report of a new transcript variant

https://doi.org/10.1016/j.humimm.2017.02.008Get rights and content

Abstract

The IκBζ protein (NFKBIZ gene) is a nuclear inhibitor of NF-κB and plays an important role in the pathogenesis of Psoriasis (Psor). We sought to determine whether common NFKBIZ variants were associated with the risk of developing Psor. A total of 392 patients and 336 controls were genotyped for a common intron 10 indel that could affect pre-mRNA splicing. We found a significantly higher frequency of the insertion among the cw6-positive patients (p = 0.01). Cw6-positive + intron 10 ins/ins were significantly more frequent in the patients (OR = 3.61). The analysis of the cDNA from leukocytes showed a NFKBIZ transcript lacking exon 10, present in all the tested samples. This new alternative transcript lacks a domain predicted to interact with the NFKB1/p50 protein. Functional studies to define the effect of this alternative transcript on the regulation of the NF-κB pathway are necessary.

Introduction

NF-κB is a transcription factor that regulates the expression of many genes implicated in inflammation, apoptosis, cell proliferation and differentiation. NF-κB has been implicated in the pathogenesis of Psoriasis (Psor) [1], [2], [3]. The role of NF-κB in Psor is supported by studies that reported its differential expression in normal vs. Psor skin. But also, by studies that showed that the inhibition of NF-κB by several compounds ameliorates the skin inflammation [4], [5], [6].

The NF-κB activity is regulated by its cytoplasmic binding to several inhibitors (IκB) that block the translocation to the nucleus. In addition, atypical IκB proteins are located in the nucleus, and among these the IκBζ (nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor zeta protein) regulates the NF-κB activity as a transcription factor by preventing its binding to the DNA. IκBζ can also acts itself as a transcription factor, and since no DNA binding motifs have been recognised it has been proposed that IκBζ could promote gene expression through atypical mechanisms such as chromatin remodelling [7], [8], [9]. IκBζ is induced by several pro-inflammatory molecules, including IL-17A, and might thus play an important role in the development of Th17 cells and the regulation of pathways in which the Th17 are implicated [10], [11], [12]. Therefore, IκBζ has been identified as a new and important player in the pathogenesis of Psor through its regulation of the IL-17 pathway [13], [14], [15].

Psor is a chronic inflammatory skin disease in which acquired/environmental and inherited/genetic risk factors interplay to define the individual’s risk [16]. Common and rare variants in several candidate genes are associated with the risk of developing Psor, and also with the clinical type, age of onset, severity, or the risk for psoriatic arthritis (PsA) [17], [18]. To date, the Major Hystocompatibilty HLA_Cw6∗0602 allele is the best characterized genetic risk factor for Psor [19], [20]. In addition to this well recognised genetic association other immunologically relevant genes have been linked to the risk for Psor, including components of the NF-κB pathway [21], [22], [23], [24], [25], [26]. Recently, sequence variants in the chromosome region 3q12.3 where the NFKBIZ maps have been linked to the expression level of IκBζ and associated with the risk of developing Psor [27].

Our aim was to investigate the association of common intragenic NFKBIZ polymorphisms with the risk of developing Psor, and whether these variants have a significant effect on disease severity and the risk of developing arthritis.

Section snippets

Study population and data collection

This study was approved by the Ethical Committee of Hospital Universitario Central Asturias (HUCA). All the participants were Caucasians from the region of Asturias (Northern Spain, total population 1 million), older than 18 years, and gave their written informed consent to participate in the study. The patient’s cohort was registered as a Biobank Collection by the Spanish Instituto Salud Carlos III (reference C.0003441).

The study involved a total of 392 patients with chronic plaque Psor (mean

NFKBIZ variants in Psor patients and controls

The allele and genotype frequencies for the two variants did not differ between the two groups (Table 2; suppl. Table 2). Among the patients, we did not find differences between the onset age, disease severity, or PsA groups. We found a significant higher frequency of the intron 10 insertion allele among the cw6-positive patients (p = 0.01) with a recessive effect (p = 0.02, ins/ins vs ins/del + del/del). We also calculated the frequencies of the haplotypes defined by the two indel polymorphisms.

Discussion

Our study showed a significant difference in the frequency of a common NFKBIZ polymorphism between Cw6 positive and negative Psor patients. Although the frequency of the intron 10 insertion allele was higher among the patients compared to the controls, the difference was non-significant. The HLA-Cw6 is the best characterized Psor-risk variant, and phenotypic and genotypic differences between Cw6+ and negative cases have been reported [19]. Because the large effect of this HLA allele, the

Contributorship

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

Funding sources

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

Conflict of interest

PCS has received an unrestricted, educational grant from Abbvie and Novartis, and received honoraria, educational support or acts as speaker for Abbvie, Celgene, Pfizer, Lilly, MSD, and Janssen.

Acknowledgements

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

References (33)

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