Functional significance of gene polymorphisms in the promoter of myeloid differentiation-2

Ann Surg. 2007 Jul;246(1):151-8. doi: 10.1097/01.sla.0000262788.67171.3f.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • China
  • Female
  • Gene Expression*
  • Genotype
  • Humans
  • Inflammation / genetics*
  • Inflammation / immunology
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Antigen 96 / genetics*
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic / genetics*
  • RNA, Messenger / genetics*
  • Reference Values
  • Retrospective Studies
  • Transcription, Genetic


  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • RNA, Messenger