Interleukin 1 receptor antagonist gene variable number of tandem repeats polymorphism and cutaneous melanoma

Abstract

Immunity and cytokines serve crucial roles in cutaneous melanoma. The present study investigated whether a variable number tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL-1RA) gene (IL-1RN) located in intron 2 (rs2234663) is associated with cutaneous melanoma. A total of 515 subjects were studied, 133 of which were cutaneous melanoma cases (72 stage I+II non-metastatic melanoma cases and 61 stage III+IV metastatic melanoma cases), and 382 subjects were matching healthy controls from the Friuli-Venezia-Giulia Region located in Northeast Italy, an area with a high melanoma incidence. The IL-1RN-VNTR polymorphism was determined by DNA fragment length analysis following PCR amplification. According to the number of 86-bp repeats, five different IL-1RN alleles were identified: Allele 1 (4-repeats), allele 2 (2-repeats, short allele), allele 3 (5-repeats), allele 4 (3-repeats) and allele 5 (6-repeats). Alleles with three or more 86-bp repeats, i.e. allele 1, 3, 4 and 5 were collectively denoted as long (L) repeats. The present study revealed that IL-1RN-VNTR 1/2 and 2/L genotypes were more frequent among patients with cutaneous melanoma (43.6 and 45.1%, respectively) compared with healthy controls [29.6 and 30.6%, respectively; odds ratio (OR), 1.84; CI, 1.22-2.77; P=0.003; and OR, 1.66; CI, 1.24-2.79; P=0.002, respectively]. Conversely, the IL-1RN-VNTR 1/1 genotype was less frequent among melanoma cases (45.9%) compared with healthy controls (57.9%; OR, 0.62; CI, 0.41-0.92; P=0.017). Comparison of metastatic vs. non-metastatic melanoma cases identified no significant differences. The present study first demonstrated that carriage of the 1/1 IL-1RN-VNTR genotype was protective, whereas 1/2 and 2/L was a risk factor for patients with cutaneous melanoma vs. healthy controls. The short allele 2 was associated with higher expression levels of IL-1RA, a potent competitive inhibitor of the proinflammatory cytokines IL-1α and IL-1β. VNTR-IL-1RN polymorphism may affect susceptibility to melanoma and, thus, it is a potential novel diagnostic biomarker for melanoma. The present study increased the understanding of genetic melanoma susceptibility/carcinogenesis, and may indicate novel strategies in the personalized prevention of cutaneous melanoma.

Immune gene polymorphisms associated with poor response to platelet transfusion and recombinant factor VII administration in Glanzmann thrombasthenia

“…In contrast to our findings, a cohort study by Baffuno et al, 34 exploring the association between IL-10 and TNF-α polymorphism and inhibitors development in haemophilia patients, did not observe any significant differences in the frequency of these two polymorphisms.…”

The role of occlusion and micro-incontinence in the pathogenesis of penile lichen sclerosus: an observational study of pro-inflammatory cytokines’ gene expression

“…IL-1 receptor antagonist (IL-1RN, alias: IL-1RA) acts antagonistically to IL-1; therefore, it has revealed anti-inflammatory properties [ 11 ]. This prevents the binding of the IL-1α and IL-1β to IL-1R1, which is a key step in the activation of the cascade of kinases that activates NF-kB and cyclooxygenase-2 (COX-2) [ 12 ]. Interleukin 6 is known as a pro-inflammatory cytokine secreted by monocytes and macrophages.…”

The Interleukin-1 (IL-1) Superfamily Cytokines and Their Single Nucleotide Polymorphisms (SNPs)

“…The classical IL-1RN gene has four exons and, currently, about 140 SNPs have been recorded for this gene [ 275 ]. The earliest reports and the most common polymorphisms of this gene were described as a penta-allelic 86 bp variable number tandem repeat (VNTR), located within intron 2 of the IL10Ra gene or within intron 3 of the extended gene containing the additional 5′ exon encoding IL1-Ra1 [ 308 , 309 ]. For this VNTR, IL1RN∗1 contains four repeats of the 86 bp in tandem, while IL1RN∗2 two repeats, and IL1RN∗3 five repeats [ 310 ].…”