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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

Division of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis, University Hospital (S.L.F.), 1211 Geneva, Switzerland; Center for Genetics of Cardiovascular Disorders, Rayne Institute, Royal Free and University College London Medical School (L.A.-L., S.E.H.), WC1E 6BT London, United Kingdom; INSERM, U-403, Hôpital E. Herriot and Synarc (P.G.), 69003 Lyon, France; and Divisions of Endocrinology and Metabolism and Gerontology, University of Pittsburgh Medical Center (S.L.G.), Pittsburgh, Pennsylvania 15260

Address all correspondence and requests for reprints to: Dr. Serge Ferrari, Division des Maladies Osseuses, Département de Médecine Interne, Hôpitaux Universitaires de Genève, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail: serge.ferrari{at}medecine.unige.ch.

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 GC, that alone and in combination influence IL-6 activity in vitro and in vivo. The association of IL-6 -572 genotypes and -572/-174 GC 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.

This work was supported by grants (to S.L.G.) from the NIH (RO1-AG-13069) and the Harvard Thorndike General Clinical Research Center (MO1-RR-01032), and by Grants RG-95007 and SP-96003 from the British Heart Foundation (to S.E.H. and H.M.).

Abbreviations: BMD, Bone mineral density; CRP, C-reactive protein; CTx, C-terminal cross-linking of type I collagen; sCTx, serum C-terminal cross-linking of type I collagen; uCTx, urinary C-terminal cross-linking of type I collagen.

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