Promoter Polymorphisms of the Genes Encoding Tumor Necrosis Factor-α and Interleukin-1β are Associated with Different Subtypes of Psoriasis Characterized by Early and Late Disease Onset

Abstract

The psoriatic inflammatory process is characterized by an overexpression of pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1beta compared with a relative deficiency of anti-inflammatory factors such as interleukin-10 and the interleukin-1 receptor antagonist (interleukin-1Ra). Gene polymorphisms that affect cytokine production may contribute to the disease-associated cytokine imbalance and influence susceptibility to psoriasis. Here, we investigated the relationship between polymorphisms in the genes encoding for tumor necrosis factor-alpha (G-238A, G-308A), interleukin-1beta (C-511T, T+3953C), and interleukin-1Ra (intron 2), and cytokine production in peripheral blood mononuclear cells of healthy donors, and analyzed the distribution of these polymorphisms in patients with psoriasis vulgaris (n = 231) and healthy controls (n = 345). Carriage of tumor necrosis factor A-238 allele 2 (-238*A) was associated with increased production of tumor necrosis factor-alpha in response to lipopolysaccharide in vitro, and with early onset disease (< 40 y), especially in male patients with psoriasis [32% vs 7% in male controls; odds ratio = 6.78, 95% confidence interval = (3.18-15.15), p(adjusted) = 2 x 10(-7)]. Carriage of the interleukin-1B-511*1 (-511*C) homozygous genotype was associated with increased production of interleukin-1Ra in response to lipopolysaccharide and interleukin-10, and with late onset psoriasis [> or = 40 y; 61% vs 44% in controls; odds ratio = 2.04, 95% confidence interval = (1.19-3.53), p(adjusted) = 0.0419]. These findings indicate that gene polymorphisms associated with altered cytokine responses in vitro may modify age of onset of psoriasis. They also provide further evidence that patients with early and late onset psoriasis differ in their genetic background.

TNF polymorphisms in psoriasis: Association of psoriatic arthritis with the promoter polymorphism TNF*‐857 independent of the PSORS1 risk allele

“…As the main finding, these studies consistently showed that carriage of the allele TNF*-238A in Caucasians is ϳ3-5 times as common among patients with psoriasis vulgaris as among healthy individuals (4-6). High carriage rates were particularly observed among patients with early-onset psoriasis (7). Case-control studies in patients with psoriatic arthritis (PsA) yielded similar results, although the association with TNF*-238A appeared to be weaker (8).…”

“…Thus, the present LD analyses and estimated haplotype frequencies indicate that a considerable percentage of carriers of the PSORS1 risk allele will also carry TNF*-238A. However, the predominant role of PSORS1 does not exclude the possibility that TNF-238 acts as a minor locus, influencing the disease course and features such as age at onset (7). For another TNF SNP at position -308 that was included in our study, we did not detect any association with PsA, a finding consistent with the results of previous investigations (8,9).…”

Investigation of cytokine gene polymorphisms in patients with psoriasis vulgaris

“…Başlangıç yaşı ile sitokin gen polimorfizmi incelendiğinde ise İFN-γ AA (düşük üretici) genotipi erken başlangıçlı hastalarda yüksek bulunmasına rağmen Bonferroni testi ile anlamlılığı ortaya konulamadı.TNF-α, psoriasis patogenezinde önemli bir proenflamatuvar sitokindir. Farklı popülasyonlarda yapılan çalışmalar TNF-α promotor bölgesinin -238 pozisyonundaki GG genotipinin psoriasis, GA genotipinin tip 1 psoriasis ve AA genotipi ile A allelinin erken başlangıç yaşı ile ilişkisini göstermişlerdir 4,7,8,[18][19][20][21] . Bunların aksine çalışmamızda TNF-α gen polimorfizmi ile hastalık, başlangıç yaşı, hastalığın şiddeti ve artrit gelişimi arasında anlamlı bir fark bulunamadı.…”

“…Bu iki grup sitokin birbirlerinin antagonisti olarak çalışırlar. Psoriasiste Th1 ve Th2 sitokinleri arasındaki denge Th1 yönünde değişmiştir 4 . Sitokin ekspresyonundaki bozukluklar deri lezyonlarının başlangıcından sorumludur.…”

Genetic Factors in Immunopathogenesis of Psoriasis and Psoriatic Arthritis

“…Среди поляков предрас-положенность и фенотип псориаза ассоциирован с аллельным вариантом -238*А -генотипы с его присутствием в три раза чаще встречаются у боль-ных с ранним дебютом заболевания. В немецкой популяции аллельный вариант -238*А также ас-социирован с ранним началом ПС, особенно сре-ди мужчин [53].…”