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.
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.
Ferrari
S L
SL
Division of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis, University Hospital, 1211 Geneva, Switzerland. serge.ferrari@medecine.unige.ch
Ahn-Luong
L
L
Garnero
P
P
Humphries
S E
SE
Greenspan
S L
SL
D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000502:physiology; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology; D002097:C-Reactive Protein / Q000032:analysis*; D003545:Cysteine; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D005998:Glycine; D006239:Haplotypes; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000235:genetics*; D015663:Osteoporosis, Postmenopausal / Q000097:blood* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics*
D015415:Biomarkers; D015850:Interleukin-6; D002097:C-Reactive Protein; D003545:Cysteine; D005998:Glycine