Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women

J Clin Endocrinol Metab. 2003 Jan;88(1):255-9. doi: 10.1210/jc.2002-020092.


IL-6 is a pleiotropic cytokine that plays a critical role in bone resorption. We describe two allelic variants in the IL-6 promoter, -572 and -174 G-->C, that alone and in combination influence IL-6 activity in vitro and in vivo. The association of IL-6 -572 genotypes and -572/-174 G-->C haplotypes with serum C-reactive protein (CRP), serum and urinary C-terminal cross-linking of type I collagen (a marker of bone resorption), and osteocalcin (a marker of bone formation) was investigated in a cohort of healthy postmenopausal women (n = 495; mean age +/- SD, 72 +/- 5.7 yr). Among IL-6 -572 genotypes, CRP was 37% higher (P = 0.02) and urinary C-terminal cross-linking of type I collagen was 20% higher (P = 0.01) in the presence of the C allele, whereas serum osteocalcin was not different. IL-6 -572/-174 haplotypes (G/C, G/G, and C/G) were significantly associated with all biochemical markers, and additive effects of the two polymorphic loci were found. Thus, there was a significant increase in the level of CRP (up to +79%; P = 0.007) and bone resorption markers (up to +32%; P = 0.017) with a decreasing number (from four to one) of IL-6 protective alleles -572G and -174C. In addition, there was a trend for lower age-adjusted bone mineral density at the lumbar spine in subjects with less IL-6 protective alleles (up to -9.6%; P = 0.037; P = 0.08 after further adjustment for weight). In conclusion, we describe two functional polymorphisms in the IL-6 gene regulatory region associated with IL-6 activity in postmenopausal women, both systemically (CRP) and locally in bone. As such, IL-6 polymorphisms are able to influence the risk of osteoporosis as well as other chronic disorders involving IL-6 activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Alleles
  • Amino Acid Substitution
  • Biomarkers / blood
  • Bone Density / physiology
  • Bone Remodeling / genetics
  • Bone Remodeling / physiology
  • C-Reactive Protein / analysis*
  • Cysteine
  • Female
  • Gene Expression Regulation / genetics*
  • Genotype
  • Glycine
  • Haplotypes
  • Humans
  • In Vitro Techniques
  • Interleukin-6 / genetics*
  • Osteoporosis, Postmenopausal / blood*
  • Osteoporosis, Postmenopausal / genetics*
  • Polymorphism, Genetic / physiology*
  • Promoter Regions, Genetic / genetics*


  • Biomarkers
  • Interleukin-6
  • C-Reactive Protein
  • Cysteine
  • Glycine