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

Abstract

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 week24. 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 exon10 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.