A Mendelian Randomization Study of Cardiovascular Proteins, Immune Cell Traits, and Lifestyle Factors
Abstract
We aimed to investigate the causal relationship between cardiovascular-related proteins and osteoporosis and to assess the influence of immune cell traits and lifestyle factors such as smoking and alcohol consumption on osteoporosis risk.
A two-sample Mendelian randomization (MR) approach was employed using publicly available genome-wide association study (GWAS) data. Univariable and multivariable MR analyses were conducted using the inverse variance weighted (IVW) method to evaluate causal effects. Additional sensitivity analyses were performed to validate findings.
Three cardiovascular proteins showed significant associations with osteoporosis and pathological fractures: TNF-related apoptosis-inducing ligand receptor 2 (OR=0.10), TNF-related activation-induced cytokine (OR=2.90), and C-C motif chemokine 4 (OR=1.12). Lifestyle factors, including household tobacco smoke exposure, daily smoking quantity, and alcohol consumption, were also significantly associated with increased osteoporosis risk. Immune cell traits were identified as potential mediators in the relationship between cardiovascular proteins and osteoporosis.
This study highlights a novel link between cardiovascular health and osteoporosis, suggesting that specific proteins increase risk, while immune traits mediate this effect, and lifestyle factors are independent risk factors. These findings underscore the importance of integrated strategies addressing inflammation and lifestyle in osteoporosis prevention and management.
2. Kim KT, Lee YS, Han I. The Role of Epigenomics in Osteoporosis and Osteoporotic Vertebral Fracture. Int J Mol Sci. 2020;21(24)
3. Yu J, Brenneman SK, Sazonov V, Modi A. Reasons for not initiating osteoporosis therapy among a managed care population. Patient Prefer Adher. 2015;9:821-30.
4. Zhang W, Liu Y, Luo Y, Shu X, Pu C, Zhang B, et al. New insights into the role of long non-coding RNAs in osteoporosis. Eur J Pharmacol. 2023;950:175753.
5. Wang CY, Fu SH, Yang RS, Shen LJ, Wu FL, Hsiao FY. Age- and gender-specific epidemiology, treatment patterns, and economic burden of osteoporosis and associated fracture in Taiwan between 2009 and 2013. Arch Osteoporos. 2017;12(1):92.
6. Lin YH, Teng M. Comparing self-assessment, functional, and anthropometric techniques in predicting osteoporosis. Arch Osteoporos. 2020;15(1):132.
7. Ercan S, Ince PT, Baskurt Z, Baskurt F. Health belief model - male osteoporosis: a cross-sectional study. Cent Eur J Publ Heal. 2023;31(3):184-90.
8. Skrivankova VW, Richmond RC, Woolf B, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. Jama-J Am Med Assoc. 2021;326(16):1614-21.
9. Folkersen L, Gustafsson S, Wang Q, Hansen DH, Hedman AK, Schork A, et al. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nat Metab. 2020;2(10):1135-48.
10. Orru V, Steri M, Sidore C, Marongiu M, Serra V, Olla S, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet. 2020;52(10):1036-45.
11. Lane JM, Russell L, Khan SN. Osteoporosis. Clin Orthop Relat R. 2000;(372):139-50.
12. Kelsey JL. Risk factors for osteoporosis and associated fractures. Public Health Rep. 1989;104 Suppl(Suppl):14-20.
13. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40(3):740-52.
14. Yang M, Wan X, Zheng H, Xu K, Xie J, Yu H, et al. No Evidence of a Genetic Causal Relationship between Ankylosing Spondylitis and Gut Microbiota: A Two-Sample Mendelian Randomization Study. Nutrients. 2023;15(4)
15. Bowden J, Davey SG, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40(4):304-14.
16. Hemani G, Tilling K, Davey SG. Orienting the causal relationship between imprecisely measured traits using GWAS summary data. Plos Genet. 2017;13(11):e1007081.
17. Lampropoulos CE, Papaioannou I, D'Cruz DP. Osteoporosis--a risk factor for cardiovascular disease? Nat Rev Rheumatol. 2012;8(10):587-98.
18. Azeez TA. Osteoporosis and cardiovascular disease: a review. Mol Biol Rep. 2023;50(2):1753-63.
19. Wang LT, Chen LR, Chen KH. Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview. Int J Mol Sci. 2023;24(6)
20. Peng M, Wang Y, Qiang L, Xu Y, Li C, Li T, et al. Interleukin-35 Inhibits TNF-alpha-Induced Osteoclastogenesis and Promotes Apoptosis via Shifting the Activation From TNF Receptor-Associated Death Domain (TRADD)-TRAF2 to TRADD-Fas-Associated Death Domain by JAK1/STAT1. Front Immunol. 2018;9:1417.
21. Boyce BF, Li J, Yao Z, Xing L. Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis. Endocrinol Metab. 2023;38(5):504-21.
22. Hu X, Ma S, Chen L, Tian C, Wang W. Association between osteoporosis and cardiovascular disease in elderly people: evidence from a retrospective study. Peerj. 2023;11:e16546.
23. Bellasi A, Raggi P. Bone metabolism and cardiovascular disease: An overlooked association? Atherosclerosis. 2021;335:87-8.
24. Wang X, Wang M, Cui X, Li Z, Guo S, Gao F, et al. Antiosteoporosis effect of geraniin on ovariectomy-induced osteoporosis in experimental rats. J Biochem Mol Toxic. 2021;35(6):1-8.
25. Li Z, Chen C, Zhu X, Li Y, Yu R, Xu W. Glycyrrhizin Suppresses RANKL-Induced Osteoclastogenesis and Oxidative Stress Through Inhibiting NF-kappaB and MAPK and Activating AMPK/Nrf2. Calcified Tissue Int. 2018;103(3):324-37.
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Keywords | ||
Cardiovascular proteins Immune cell Mendelian randomization analysis Osteoporosis |
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