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  • Title: Functional significance of gene polymorphisms in the promoter of myeloid differentiation-2.
    Author: Gu W, Shan YA, Zhou J, Jiang DP, Zhang L, Du DY, Wang ZG, Jiang JX.
    Journal: Ann Surg; 2007 Jul; 246(1):151-8. PubMed ID: 17592304.
    Abstract:
    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.
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