Abstract
Previous studies have indicated that the monocyte chemo-attractant protein 1 (MCP-1), also referred to as C-C motif chemokine ligand 2 (CCL2), plays a significant role in the pathogenesis of sepsis, and this study investigated the clinical relevance of two MCP-1 gene polymorphisms on sepsis onset and progression. The Multiplex SNaPshot genotyping method was used to detect MCP-1 gene polymorphisms in the Chinese Han population (403 sepsis patients and 400 controls). MCP-1 mRNA expression levels were measured using real-time quantitative PCR, and enzyme-linked immunosorbent assays were used to analyze MCP-1, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and interleukin-1 beta (IL-1β) plasma concentrations. The rs1024611 polymorphism analysis showed lower frequencies of minor homozygous genotype (AA) and allele (A) in sepsis patients compared to the healthy controls (19.4% vs. 31.5%, P = 0.0001 and 45.9% vs. 54.8%, P = 0.0004, respectively). And the frequencies of GG genotype and G allele were lower in sepsis patients compared to the controls (19.6% vs. 31.3%, P = 0.0002 and 46.0% vs. 54.5%, P = 0.0007, respectively). The rs1024611 AG/GG and rs2857656 GC/CC genotypes were both overrepresented in patients with severe sepsis (both P = 0.0005) and septic shock (P = 0.010 and P = 0.015, respectively) compared to the patients with mild sepsis. Moreover, among sepsis patients, the rs1024611 AG/GG and rs2857656 GC/CC carriers exhibited significant increases in expression levels of MCP-1 (P = 0.025), TNF-α (P = 0.034) and IL-6 (P = 0.043) compared with the rs1024611 AA or rs2857656 GG carriers. This study provides valuable clinical evidence that the MCP-1/CCL2 polymorphisms rs1024611 and rs2857656 are associated with sepsis susceptibility and development. We conclude that MCP-1/CCL2 plays a significant role in the pathogenesis of sepsis, which has potentially important therapeutic implications.
Highlights
Sepsis is a systemic inflammatory disease resulting from a harmful response to microbial infection [1,2,3]
We identified additional stratifications indicating that the rs1024611 G allele and rs2857656 C allele were both overrepresented among the severe sepsis/septic shock subgroups compared with the mild sepsis subgroup, suggesting a possible role for rs1024611 A>G and rs2857656 G>C in promoting sepsis progression
Several studies have shown that the expression levels of Monocyte chemo-attractant protein 1 (MCP-1) are markedly increased in various murine models of sepsis, which reflect the organ dysfunction and mortality seen in sepsis patients [15, 38]
Summary
Sepsis is a systemic inflammatory disease resulting from a harmful response to microbial infection [1,2,3]. Studies have shown that antibody neutralization or a specific antagonist of MCP-1 in mouse models of sepsis can decrease the septic response and are beneficial to survival, making MCP-1 a promising potential therapeutic target for sepsis [20,21,22]. Taken together, these lines of evidence indicate that continuous activation of MCP-1 plays a role in the pathogenesis and progression of sepsis
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