Obesity and osteoporosis share common physiological factors, including the presence of atherosclerosis, a risk factor for cardiometabolic disease, as well as a common progenitor that differentiates into both adipocytes and osteoblasts. Among the 23 polymorphisms associated with bone mineral density (BMD) in recent genome-wide association studies (GWASs), an Osterix polymorphism has been identified and associated with childhood obesity in girls. Therefore, we focused on elucidating polymorphisms associated with adulthood obesity in a sex-dependent manner among the previously published BMD-associated polymorphisms from GWASs. We performed 2 screenings of 18 BMD-associated polymorphisms for obesity-related traits in 2,362 adults aged >20 years. We excluded 13 polymorphisms showing deviations from Hardy–Weinberg equilibrium or no association with obesity-related traits (body mass index, waist circumference (WC), and waist-to-hip ratio). Among 5 selected polymorphisms (rs9594738 of RANKL, rs17066364 of NUFIP1, rs7227401 of OSBPL1A, and rs1856057 and rs2982573 of ESR1) analyzed, 2 polymorphisms (rs9594738 and rs17066364) were associated with obesity-related traits. We found sex-dependent associations such that the 4 polymorphisms (excluding rs9594738 of RANKL) were associated with abdominal traits such as WC and waist-to-hip ratio only in men. In addition, when the combined genetic risk score (GRS) for WC increase was calculated with 4 SNPs (rs9594738, rs17066364, rs7227401, and rs1856057) exhibiting similar trends for both sexes, the magnitude of the GRS effect for the WC increase was larger in men than in women (effect size = 0.856 cm, P = 0.0000452 for men; effect size = 0.598 cm, P = 0.00228 for women). In summary, we found 4 polymorphisms, previously related to osteoporosis, to be associated to obesity-related traits in a sex-dependent manner in Korean adults, particularly in men.
Ravn P, Cizza G, Bjarnason NH, Thompson D, Daley M, et al. (1999) Low body mass index is an important risk factor for low bone mass and increased bone loss in early postmenopausal women. Early Postmenopausal Intervention Cohort (EPIC) study group. J Bone Miner Res 14: 1622–1627.
Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JC (2000) Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol 20: 1926–1931.
Farhat GN, Newman AB, Sutton-Tyrrell K, Matthews KA, Boudreau R, et al. (2007) The association of bone mineral density measures with incident cardiovascular disease in older adults. Osteoporos Int 18: 999–1008.
Kiel DP, Kauppila LI, Cupples LA, Hannan MT, O'Donnell CJ, et al. (2001) Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study. Calcif Tissue Int 68: 271–276.
Liu YZ, Pei YF, Liu JF, Yang F, Guo Y, et al. (2009) Powerful bivariate genome-wide association analyses suggest the SOX6 gene influencing both obesity and osteoporosis phenotypes in males. PLoS One 4: e6827.
Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, et al. (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41: 1199–1206.
Hsu YH, Zillikens MC, Wilson SG, Farber CR, Demissie S, et al. (2010) An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits. PLoS Genet 6: e1000977.
Paternoster L, Lorentzon M, Vandenput L, Karlsson MK, Ljunggren O, et al. (2010) Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet 6: e1001217.
Duncan EL, Danoy P, Kemp JP, Leo PJ, McCloskey E, et al. (2011) Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 7: e1001372.
Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, et al. (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41: 527–534.
Cornelis MC, Qi L, Zhang C, Kraft P, Manson J, et al. (2009) Joint effects of common genetic variants on the risk for type 2 diabetes in U.S. men and women of European ancestry. Ann Intern Med 150: 541–550.
Heid IM, Jackson AU, Randall JC, Winkler TW, Qi L, et al. (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42: 949–960.
Alonso CG, Curiel MD, Carranza FH, Cano RP, Perez AD (2000) Femoral bone mineral density, neck-shaft angle and mean femoral neck width as predictors of hip fracture in men and women. Multicenter Project for Research in Osteoporosis. Osteoporos Int 11: 714–720.
Xie H, Xie PL, Wu XP, Chen SM, Zhou HD, et al. (2011) Omentin-1 attenuates arterial calcification and bone loss in osteoprotegerin-deficient mice by inhibition of RANKL expression. Cardiovasc Res 92: 296–306.
Yan D, Lehto M, Rasilainen L, Metso J, Ehnholm C, et al. (2007) Oxysterol binding protein induces upregulation of SREBP-1c and enhances hepatic lipogenesis. Arterioscler Thromb Vasc Biol 27: 1108–1114.
Gu JM, Xiao WJ, He JW, Zhang H, Hu WW, et al. (2009) Association between VDR and ESR1 gene polymorphisms with bone and obesity phenotypes in Chinese male nuclear families. Acta Pharmacol Sin 30: 1634–1642.