Abstract
IntroductionNuclear factor-κB (NF-κB) family plays an important role in the development of sepsis in critically ill patients. Although several single nucleotide polymorphisms (SNPs) have been identified in the NF-κB family genes, only a few SNPs have been studied.MethodsA total of 753 patients with major blunt trauma were included in this study. Tag SNPs (tSNPs) were selected from the NF-κB family genes (NFKB1, NFKB2, RELA, RELB and REL) through construction of haplotype blocks. The SNPs selected from genes within the canonical NF-κB pathway (including NFKB1, RELA and REL), which played a critical role in innate immune responses were genotyped using pyrosequencing method and analyzed in relation to the risk of development of sepsis and multiple organ dysfunction (MOD) syndrome. Moreover, the rs842647 polymorphism was analyzed in relation to tumor necrosis factor α (TNF-α) production by peripheral blood leukocytes in response to bacterial lipoprotein stimulation.ResultsEight SNPs (rs28362491, rs3774932, rs4648068, rs7119750, rs4803789, rs12609547, rs1560725 and rs842647) were selected from the NF-κB family genes. All of them were shown to be high-frequency SNPs in this study cohort. Four SNPs (rs28362491, rs4648068, rs7119750 and rs842647) within the canonical NF-κB pathway were genotyped, and rs842647 was associated with sepsis morbidity rate and MOD scores. An association was also observed between the rs842647 A allele and lower TNF-α production.Conclusionsrs842647 polymorphism might be used as relevant risk estimate for the development of sepsis and MOD syndrome in patients with major trauma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0836-6) contains supplementary material, which is available to authorized users.
Highlights
Nuclear factor-κB (NF-κB) family plays an important role in the development of sepsis in critically ill patients
Construction of haplotype blocks and selection of single-nucleotide polymorphism (SNP) SNPs with a minor allele frequency (MAF) ≥0.05 were shown within and around the NFKB1, NFKB2, RELA, RELB and REL genes from the HapMap database for the Chinese individuals from Beijing (CHB) population (Additional file 3 and Figure 1). rs28362491, a common insertion/ deletion polymorphism (−94 insertion/deletion ATTG), though it did not form any block with other SNPs, has been identified located between two putative key promoter regulatory elements in the NFKB1 gene
The haplotype tag single-nucleotide polymorphism (htSNP) and SNPs that are indirectly measured by them are listed with corresponding r2 values
Summary
Nuclear factor-κB (NF-κB) family plays an important role in the development of sepsis in critically ill patients. Several single nucleotide polymorphisms (SNPs) have been identified in the NF-κB family genes, only a few SNPs have been studied. With great improvements in the emergency care system, survival after major trauma is common, but it is often complicated with sepsis and multiple organ dysfunction syndrome (MODS) [1]. Preventing sepsis and MODS is crucial in the treatment of patients who NF-κB family regulates genes required for both the innate and adaptive immune responses [5,6]. The canonical pathway mainly activates the transcription of many proinflammatory cytokine and chemokine genes that initiate and propagate innate immune responses [8]. The noncanonical pathway mainly regulates adaptive immune responses and lymphoid development. The pivotal role of NF-κB canonical pathway in the development of sepsis makes it an interesting candidate for genetic analysis
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