Polymorphisms of Pro-Inflammatory IL-6 and IL-1β Cytokines in Ascending Aortic Aneurysms as Genetic Modifiers and Predictive and Prognostic Biomarkers.

Letizia Scola,Carmela Rita Balistreri,Giacomo Frati,Calogera Pisano,Vincenzo Marinello,Domenico Lio,Giovanni Ruvolo,Valeria Cancila,Rosa Maria Giarratana

doi:10.3390/biom11070943

Abstract

Background: Previous studies have demonstrated that polymorphisms involved in immune genes can affect the risk, pathogenesis, and outcome of thoracic ascending aortic aneurysms (TAAA). Here, we explored the potential associations of five functional promoter polymorphisms in interleukin-6 (IL-6), IL-1B, IL-1A, IL-18, and Tumor necrosis factor (TNF)A genes with TAAA. Methods: 144 TAAA patients and 150 age/gender matched controls were typed using KASPar assays. Effects on telomere length and levels of TAAA related histopathological and serological markers were analyzed. Results: Significant associations with TAAA risk were obtained for IL-6 rs1800795G>C and IL-1B rs16944C>T SNPs. In addition, the combined rs1800795C/rs16944T genotype showed a synergic effect on TAAA pathogenesis and outcome. The combined rs1800795C/rs16944T genotype was significantly associated with: (a) higher serum levels of both cytokines and MMP-9 and -2; (b) a significant CD3+CD4+CD8+ CD68+CD20+ cell infiltration in aorta aneurysm tissues; (c) a significant shorter telomere length and alterations in telomerase activity. Finally, it significantly correlated with TAAA aorta tissue alterations, including elastic fragmentation, medial cell apoptosis, cystic medial changes, and MMP-9 levels. Conclusions: the combined rs1800795C/rs16944T genotype appears to modulate TAAA risk, pathogenesis, and outcome, and consequently can represent a potential predictive and prognostic TAAA biomarker for individual management, implementation of innovative treatments, and selection of the more proper surgical timing and approaches.

Highlights

IntroductionBiomolecules 2021, 11, 943 disease, and heart failure [2,4–6]), to other cardiovascular pathological conditions [7]
1).recommended by the current guidelines [22] (Figure 1). In line with these recent data, and for validating the associations previously observed [22], here, we aimed to investigate the potential association of functional polymorphisms in IL-6, IL-1A, IL-1B, IL-18, and Tumor necrosis factor (TNF)A genes with thoracic ascending aortic aneurysms (TAAA)
Recent studies have confirmed its role in abdominal aortic aneurysms [42,43], Here, we demonstrated the role of IL-6 and IL-1B in TAAA disease

Summary

Introduction

Biomolecules 2021, 11, 943 disease, and heart failure [2,4–6]), to other cardiovascular pathological conditions [7]. Individuals affected by chronic inflammatory disorders (i.e., autoimmune dis of 15 orders) show a significant increase in the cardiovascular susceptibility. [6] Many inflammatory pathways have been documented to contribute to CVD onset and progression, including TLR-4/NF-kβ pathway [8,9], TLR-2 [10], TGF-β1 [11], CCR5 [12], CRP show a significant increase in the cardiovascular susceptibility. Pro- and anti-inflammatory cytokines, such as interleukin-(IL)-10 [14] and pathways have been documented to contribute to CVD onset and progression, including. SNPs. In addition, the combined rs1800795C/rs16944T genotype showed a synergic effect on TAAA pathogenesis and outcome. The combined rs1800795C/rs16944T genotype was significantly associated with: (a) higher serum levels of both cytokines and MMP-9 and -2; (b) a significant

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