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

Area of Science:

• Immunodermatology
• Pharmacogenetics
• Molecular Biology

Background:

• Nuclear factor (NF)-κB and tumor necrosis factor (TNF) pathways are crucial in psoriasis pathogenesis.
• NFKBIZ, a nuclear inhibitor of NF-κB, plays a key role in psoriasis.
• Genetic variations in NFKBIZ are linked to psoriasis risk and anti-TNF drug response.

Purpose of the Study:

• To investigate the association between a common NFKBIZ insertion/deletion (indel) polymorphism (rs3217713) and patient response to adalimumab.
• To compare the expression of an NFKBIZ alternative transcript in psoriasis patients with varying responses to adalimumab therapy.

Main Methods:

• Genotyping of the NFKBIZ polymorphism in 169 psoriasis patients treated with adalimumab, categorized by PASI75 response at 24 weeks.
• Analysis of HLA-CW6 allele frequencies and determination of NFKBIZ alternative transcript expression in responders versus non-responders.
• Investigation of the relationship between intronic genotype and alternative transcript levels, considering potential effects on RNA splicing.

Main Results:

• The NFKBIZ polymorphism was significantly associated with adalimumab response; deletion allele carriers were more frequent in responders (OR=2.76, p=0.015).
• The HLA-CW6 allele was also linked to a positive response (p=0.018).
• Higher, though non-significant, levels of the normal to alternative NFKBIZ transcript ratio were observed in responders and NFKBIZ insertion homozygotes.

Conclusions:

• A common NFKBIZ polymorphism significantly influences the response to adalimumab in psoriasis patients.
• These findings suggest potential for optimizing anti-TNF therapy prescription based on NFKBIZ genotype.
• Further validation in independent cohorts is necessary to confirm these pharmacogenetic associations.