Genetic Variation in TRAF3IP2 (rs13190932) and Its Association With Psoriasis, Psoriatic Arthritis, and Treatment Outcome With Methotrexate

Psoriatic arthritis (PsA) is a chronic systemic inflammatory arthritis that involves both peripheral joints and axial skeleton associated with psoriasis. The extra-articular manifestations and comorbidities are also very common. PsA develops in up to 30% of patients with psoriasis, accounting for an estimated 0.3-1.0% of the general population.

The exact aetiopathogenesis of psoriasis is not completely explained. Pathological mechanism involves skin inflammation and hyperproliferation of keratinocytes induced innate and adaptive immune cells. Genetic, immunological and environmental factors are considered the most important aetiologies . Anti-psoriatic topical preparations, such as those containingcorticosteroids or vitamin D3 analogs (usually calcipotriol [Cal]), are the mainstay of treatment of mild-to-moderate plaque psoriasis. Phototherapy and systemic drugs (administered orally or by injection or infusion) are reserved for more severe or refractory psoriasis.

Methotrexate (MTX) has remained the backbone of the treatment for moderate to severe psoriasis ever since its first use nearly half a century ago. Over the years, its high efficacy, low cost, relative ease of administration and usefulness in concomitant psoriatic arthritis have contributed in making MTX the drug of choice in managing severe psoriasis. Although the majority of patients achieve remission of disease activity with MTX, a significant proportion may experience mild and transient adverse effects. From time to time, various guidelines on the use of MTX have correctly and adequately stressed the need for strict monitoring of haematological and hepatic adverse events.

Characterizing psoriatic arthritis (PsA), mainly as an immune-mediated disease that is also affected by barrier proteins. One new PsA and psoriasis-susceptibility gene, TRAF3IP2, codes for the adaptor protein ACT1 (nuclear factor-κB activator 1), a regulator of the NF-κB pathway involved in IL-17 signaling. We were able to identify the common coding variant p.Asp10Aspn as the disease-causing allele with evidence from association findings at single nucleotide polymorphism (SNP) and haplotype levels, as well as binding studies of ACT1 with its interaction partner TRAF6.

TRAF3 is one of the most versatile members of the TRAF family. It is an intracellular protein that primarily acts as an adaptor protein with a large variety of binding partners. TRAF3 interacting protein 2 (TRAF3IP2), also called CIKS or Act1, is a key intermediate in the normal inflammatory response and is involved in the pathogenesis of various autoimmune and inflammatory diseases .Furthermore, TRAF3IP2 is a protein acting downstream of the IL-17 receptor that binds to and stabilizes mRNAs encoding key inflammatory proteins.