Abstract
BackgroundA cross-talk between Toll-like receptor 4 (TLR4) and matrix metalloproteinase 9 (MMP9) plays a vital role in aortic pathophysiology. The objective of this study was to evaluate the interactions between TLR4 and MMP9 polymorphisms in the risk of aortic aneurysm (AA) and its subtypes.MethodsKASP method was used to detect polymorphisms of TLR4 (rs11536889 and rs1927914) and MMP9 (rs17576) in 472 AA patients and 498 controls. According to location and size, AA patients were further classified into abdominal AA (AAA), thoracic AA (TAA), and large AA (>5.0 cm), small AA(≤5.0 cm), respectively.ResultsThe significant interaction effect of TLR4rs1927914 with MMP9rs17576 polymorphisms was observed for the risk of TAA (Pinteraction = 0.038, OR = 6.186) and large AA (Pinteraction = 0.044, OR = 5.892). There were epistatic effects between TLR4rs1927914 and MMP9rs17576 polymorphisms on the risk of overall AA, AAA, TAA and large AA when they were present together. Moreover, the cumulative effects of the pairwise interaction TLR4rs1927914-MMP9rs17576 were associated with an increased risk of overall AA (Ptrend = 0.032) and AAA (Ptrend = 0.031).ConclusionsThe novel interaction between TLR4rs1927914 and MMP9rs17576 polymorphisms could increase the risk of AA disease or its subtypes by exerting epistatic and cumulative effects.
Highlights
A cross-talk between Toll-like receptor 4 (TLR4) and matrix metalloproteinase 9 (MMP9) plays a vital role in aortic pathophysiology
As shown in Additional file 2: Table S2, there were no significant associations of TLR4 rs11536889 and rs1927914 polymorphisms with the risk of aortic aneurysm (AA) and its subtypes (P > 0.05) in the general and subgroup analysis stratified by AA location and size
Two-way interactions between polymorphisms of TLR4 and MMP9 In the two-way interaction analyses with a combined genotype containing the most common Single nucleotide polymorphism (SNP) for each gene, the most significant interaction was between dominant genetic model of TLR4rs1927914 and recessive genetic model of MMP9rs17576 (Table 2)
Summary
A cross-talk between Toll-like receptor 4 (TLR4) and matrix metalloproteinase 9 (MMP9) plays a vital role in aortic pathophysiology. The objective of this study was to evaluate the interactions between TLR4 and MMP9 polymorphisms in the risk of aortic aneurysm (AA) and its subtypes. Abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA) have heterogeneity in their inheritance, incidence and distribution along aorta, they share some similar pathological states and histological phenotypes, including inflammatory cell infiltration and extracellular matrix (ECM) degradation [1, 2]. Toll-like receptor 4 (TLR4) is one of the most well-characterized inflammation-related molecules, and its signaling plays a key role in triggering inflammatory response in the aortic wall [9, 10]. Because of its capacity of degrading multiple extracellular components in aortic wall, matrix metalloproteinase 9 (MMP9) has been involved in aneurysm formation [2, 17]. Multigene SNP-SNP interactions may amplify the main effect of individual SNP in complex diseases and enhance the predictive power [18]
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