CLINICAL STUDY Polymorphisms in the interleukin-6 receptor gene are associated with bone mineral density and body mass index in Spanish postmenopausal women M Bustamante 1,2,3 , X Nogue ´s 4 , L Mellibovsky 4 , L Agueda 1,2,3 , S Jurado 4 , E Ca ´ceres 4 , J Blanch 4 , R Carreras 4 , A Dı ´ez-Pe ´rez 4 , D Grinberg 1,2,3 and S Balcells 1,2,3 1 Department of Genetics, University of Barcelona, Barcelona, Spain, 2 IBUB, Barcelona, Spain, 3 CIBERER, ISCIII, Barcelona, Spain and 4 Internal Medicine, URFOA, IMIM, Hospital del Mar, Autonomous Universityof Barcelona, Barcelona, Spain (Correspondence should be addressed to S Balcells at Departament de Gene `tica, Facultat de Biologia, Universitat de Barcelona, Avinguda Diagonal, 645, E-08028 Barcelona, Spain; Email: sbalcells@ub.edu) Abstract Objective: Osteoporosis and obesity are complex diseases with a strong genetic component. Bone mineral density (BMD) and body mass index (BMI) linkage studies identified a locus at 1q21-23, where the interleukin-6 receptor (IL6R) gene is located. The IL6R and the gp130 receptors are the mediators of IL6 action. Serum levels of IL6 and sIL6R (the soluble form of IL6R) are higher in several diseases such as osteoporosis or obesity. Variants at IL6R have been associated with BMI and obesity. However, IL6R is an as-yet-unexplored osteoporosis candidate gene. Design: In the present study we analysed two polymorphisms in the IL6R promoter, K1435 C/T (rs3887104) and K208 G/A (rs4845617), and the Asp358Ala polymorphism (rs8192284), in relation to both BMD and BMI in a cohort of 559 postmenopausal Spanish women. Results: The promoter polymorphisms, K1435 C/T and K208 G/A were associated with femoral neck (FN) BMD (PZ0.011 and PZ0.025 respectively). The C-A and T-G promoter haplotypes were also associated with FN BMD. Additionally, the Asp358Ala variant was associated with lumbar spine BMD (PZ0.038). Finally, the K208 G/A polymorphism and the C-G and C-A haplotypes were associated with BMI and obesity, where GG was the risk genotype (PZ0.033 for BMI; PZ0.010 for obesity). Conclusion: These data suggest that variants in the IL6R gene are not only involved in the determination of BMI but also relevant for the determination of BMD. The IL6R gene may belong to the growing list of genes known to be involved in both phenotypes. European Journal of Endocrinology 157 677–684 Introduction Osteoporosis and obesity are complex diseases with a strong genetic component. The heritability of bone mineral density (BMD) has been estimated to be between 0.6 and 0.9 depending on body site and sex (1, 2), whereas that of body mass index (BMI), a measurement of obesity, has been calculated to be between 0.5 and 0.6 (2). Genome-wide non-parametric linkage analysis is a good method for defining quantitative trait loci (QTLs). One of these loci, identified in relation to lumbar spine (LS) BMD, BMI and type 2 diabetes mellitus (T2DM), is located at 1q21-23 (3–5). The IL6R gene maps to 1q21.3 and encodes the interleukin-6 (IL6) receptor-a. The action of IL6 is mediated through two kinds of receptors: IL6R (also known as gp80, CD126, IL-6R-1, IL-6R-A or IL-6R-a) and gp130 (CD130, IL-6R-b or oncostatin M receptor). In contrast to gp130, whose expression pattern is wide and whose ligands include several interleukins, IL6R is expressed in a more restricted cell pattern, including the osteoblast and osteoclast progenitors (6, 7), and only binds its natural ligand IL6. The IL6–IL6R complex induces the homodimeriza- tion of gp130, which mediates signalling through the JAK-STAT and ras/MAP-kinase pathways (8). IL6R may be found both as a transmembrane and as a soluble molecule (sIL6R). The latter is produced by cleavage of the former, although it may also be generated by alternative splicing (9–12). The binding capacities of IL6R and sIL6R are similar, and the IL6–sIL6R complex acts as an agonist when it binds to gp130, allowing for IL6 signalling in cells that do not express IL6R in their membranes. This process is referred to as trans- signalling (8). IL6 is a pleiotropic cytokine that has multiple effects on different cell types (8). In bone, IL6 is produced by osteoblasts, monocytes and T cells, and has an antiapoptotic and differentiating effect on osteoblasts (13–15). Also, and more importantly, IL6 induces European Journal of Endocrinology (2007) 157 677–684 ISSN 0804-4643 q 2007 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0389 Online version via www.eje-online.org