Identification of pleiotropic genetic variants affecting osteoporosis risk in a Korean elderly cohort
- 118 Downloads
Pleiotropy has important implications for understanding the genetic basis and risk assessment of osteoporosis. Our aim was to identify pleiotropic genetic variants associated with the development of osteoporosis and predict osteoporosis risk by leveraging pleiotropic variants. We evaluated the effects of 21 conventional risk factors and 185 single-nucleotide polymorphisms (SNPs) in 63 inflammation- and metabolism-related genes on osteoporosis risk in a community-based Korean cohort study of 1025 participants, the Hallym Aging Study. Ten nongenetic factors, including sex (female) and hematocrit level, and 12 SNPs across ten genes showed evidence of association with incident osteoporosis in 270 initially osteoporosis-free subjects who completed a 6-year follow up. Three gene variants, rs1801282 (PPARG-Pro12Ala, hazard ratio (HR) = 3.26, P = 0.008), rs1408282 (near EPHA7, HR = 1.87, P = 0.002), and rs2076212 (PNPLA3-Gly115Cys, HR = 2.24, P = 0.024), were associated with significant differences in survival among the three genotype groups (Pdiff = 0.042, 0.003, and 0.048, respectively). Individuals in the highest polygenic risk score tertile were 27.9 fold more likely to develop osteoporosis than those in the lowest tertile (P = 0.004). The PPARG gene in particular was a hub pleiotropic gene in the epistasis network. Our findings highlight pleiotropic modulations of metabolism- and inflammation-related genes in the development of osteoporosis and demonstrate the contribution of pleiotropic genetic variants in prediction of osteoporosis risk.
KeywordsOsteoporosis Pleiotropy Polygenic risk score Risk assessment Survival analysis
This research was supported by the Basic Science Research Program of the National. Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2014R1A1A3053168), the Bio & Medical Technology Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2012M3A9D1054450), and Hallym University Research Fund 2017 (HRF-201704-015). We are greatly thankful to all participants and staff in the Hallym Aging Study for their contribution to the project.
Compliance with ethical standards
Conflict of interest
All authors have no conflicts of interest.
- 5.Thulkar J, Singh S, Sharma S, Thulkar T (2016) Preventable risk factors for osteoporosis in postmenopausal women: systematic review and meta-analysis. J Midlife Health 7:108–113Google Scholar
- 10.Styrkarsdottir U, Thorleifsson G, Eiriksdottir B, Gudjonsson SA, Ingvarsson T, Center JR, Nguyen TV, Eisman JA, Christiansen C, Thorsteinsdottir U, Sigurdsson G, Stefansson K (2016) Two rare mutations in the COL1A2 gene associate with low bone mineral density and fractures in Iceland. J Bone Miner Res 31:173–179CrossRefGoogle Scholar
- 19.Jang SN, Choi YH, Choi MG, Kang SH, Jeong JY, Choi YJ, Kim DH (2006) Prevalence and associated factors of osteoporosis among postmenopausal women in Chuncheon: Hallym Aging Study (HAS). J Prev Med Public Health 39:389–396Google Scholar
- 30.Namvaran F, Rahimi-Moghaddam P, Azarpira N, Dabbaghmanesh MH, Bakhshayeshkaram M, Namvaran MM (2013) Changes in bone biological markers after treatment of Iranian diabetic patients with pioglitazone: no relation to polymorphism of PPAR-γ (Pro12Ala). J Res Med Sci 18:277–282Google Scholar
- 32.Yilmaz MB, Pazarbasi A, Guzel AI, Kocaturk-Sel S, Kasap H, Kasap M, Urunsak IF, Basaran S, Alptekin D, Demirhan O (2011) Association of serum sex steroid levels and bone mineral density with CYP17 and CYP19 gene polymorphisms in postmenopausal women in Turkey. Genet Mol Res 10:1999–2008CrossRefGoogle Scholar
- 34.Ferrari SL, Ahn-Luong L, Garnero P, Humphries SE, Greenspan SL (2003) 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. J Clin Endocrinol Metab 88:255–259CrossRefGoogle Scholar
- 36.Ligthart S, Vaez A, Hsu YH, Inflammation Working Group of the CHARGE Consortium, PMI-WG-XCP, LifeLines Cohort Study, Stolk R, Uitterlinden AG, Hofman A, Alizadeh BZ, Franco OH, Dehghan A (2016) Bivariate genome-wide association study identifies novel pleiotropic loci for lipids and inflammation. BMC Genomics 17:443CrossRefGoogle Scholar
- 39.Posadas-Sánchez R, López-Uribe ÁR, Posadas-Romero C, Pérez-Hernández N, Rodríguez-Pérez JM, Ocampo-Arcos WA, Fragoso JM, Cardoso-Saldaña G, Vargas-Alarcón G (2016) Association of the I148 M/PNPLA3 (rs738409) polymorphism with premature coronary artery disease, fatty liver, and insulin resistance in type 2 diabetic patients and healthy controls. The GEA study. Immunobiology. https://doi.org/10.1016/j.imbio.2016.08.008 Google Scholar