OBJECTIVE: To investigate the functional significance of the reported single nucleotide polymorphisms (SNPs) in the promoter of the myeloid differentiation-2 (MD-2) gene. SUMMARY BACKGROUND DATA: Functional gene polymorphisms of innate immune receptors have been shown to be critical determinants of the immune inflammatory response. MD-2 is an important signaling enhancer protein in the endotoxin (LPS) receptor complex. Although a total of 156 SNPs have been identified within the whole MD-2 gene, little is known about the functional significance of these SNPs. METHODS: : The possible biosignificance of 8 reported SNPs was analyzed using on-line software tools. The selected SNPs were then genotyped using a restriction fragment length polymorphism method applied to 711 healthy Chinese volunteers. Their functional effects were assessed by the observation of transcription activity, MD-2 mRNA expression, and leukocyte response to ex vitro LPS stimulation. Moreover, the clinical relevance of these SNPs was investigated in 105 patients with major trauma. RESULTS: Three SNPs (C-1625G, A-1064G, and A-475T) in the MD-2 promoter were selected based on bio-informatic analysis. Both -1625 and -1064 SNPs, rather than -475, were seen in the Chinese population, with frequencies of 19.8% (-1625G) and 34.7% (-1064G). But only the -1625 polymorphism was found to affect MD-2 promoter activity. Moreover, the expression of MD-2 mRNA and the production of TNF-alpha in whole blood leukocytes, in response to LPS stimulation, were significantly increased in subjects with the -1625 G allele. Patients who possessed the -1625 G allele were more likely to experience complications with organ dysfunction and sepsis after major trauma. All these associations were in allele-dose dependent effect. CONCLUSIONS: The MD-2/-1625 polymorphism is an important functional variant.
OBJECTIVE: To investigate the functional significance of the reported single nucleotide polymorphisms (SNPs) in the promoter of the myeloid differentiation-2 (MD-2) gene. SUMMARY BACKGROUND DATA: Functional gene polymorphisms of innate immune receptors have been shown to be critical determinants of the immune inflammatory response. MD-2 is an important signaling enhancer protein in the endotoxin (LPS) receptor complex. Although a total of 156 SNPs have been identified within the whole MD-2 gene, little is known about the functional significance of these SNPs. METHODS: : The possible biosignificance of 8 reported SNPs was analyzed using on-line software tools. The selected SNPs were then genotyped using a restriction fragment length polymorphism method applied to 711 healthy Chinese volunteers. Their functional effects were assessed by the observation of transcription activity, MD-2 mRNA expression, and leukocyte response to ex vitro LPS stimulation. Moreover, the clinical relevance of these SNPs was investigated in 105 patients with major trauma. RESULTS: Three SNPs (C-1625G, A-1064G, and A-475T) in the MD-2 promoter were selected based on bio-informatic analysis. Both -1625 and -1064 SNPs, rather than -475, were seen in the Chinese population, with frequencies of 19.8% (-1625G) and 34.7% (-1064G). But only the -1625 polymorphism was found to affect MD-2 promoter activity. Moreover, the expression of MD-2 mRNA and the production of TNF-alpha in whole blood leukocytes, in response to LPS stimulation, were significantly increased in subjects with the -1625 G allele. Patients who possessed the -1625 G allele were more likely to experience complications with organ dysfunction and sepsis after major trauma. All these associations were in allele-dose dependent effect. CONCLUSIONS: The MD-2/-1625 polymorphism is an important functional variant.
Authors: N J A Child; I A Yang; M C K Pulletz; K de Courcy-Golder; A-L Andrews; V J Pappachan; J W Holloway Journal: Biochem Soc Trans Date: 2003-06 Impact factor: 5.407
Authors: Clare E Bryant; Selinda Orr; Brian Ferguson; Martyn F Symmons; Joseph P Boyle; Tom P Monie Journal: Pharmacol Rev Date: 2015 Impact factor: 25.468
Authors: N D Loft; L Skov; L Iversen; R Gniadecki; T N Dam; I Brandslund; H J Hoffmann; M R Andersen; R B Dessau; A C Bergmann; N M Andersen; P S Andersen; S Bank; U Vogel; V Andersen Journal: Pharmacogenomics J Date: 2017-07-11 Impact factor: 3.550