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- Title
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.
- Authors
FERRARI, S. L.; AHN-LUONG, L.; GARNERO, P.; HUMPHRIES, S. E.; GREENSPAN, S. L.
- Abstract
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
Journal of Clinical Endocrinology & Metabolism, 2003, Vol 88, Issue 1, p255
- ISSN
0021-972X
- Publication type
Article
- DOI
10.1210/jc.2002-020092