Important gene–gene interaction of TNF-α and VDR on osteoporosis in community-dwelling elders

Autoři: Li-Na Liao aff001;  Chia-Ing Li aff002;  Fang-Yang Wu aff001;  Chuan-Wei Yang aff002;  Chih-Hsueh Lin aff003;  Chiu-Shong Liu aff002;  Wen-Yuan Lin aff003;  Tsai-Chung Li aff001;  Cheng-Chieh Lin aff002
Působiště autorů: Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan aff001;  Department of Medical Research, China Medical University Hospital, Taichung, Taiwan aff002;  School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan aff003;  Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan aff004;  Department of Healthcare Administration, College of Medical and Health Sciences, Asia University, Taichung, Taiwan aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226973


Gene effects on osteoporosis have been studied separately and may have been masked by gene–gene and gene–environment interactions. We evaluated gene–gene and gene–physical activity interactions of the variants of tumor necrosis factor-α (TNF-α) and vitamin D receptor (VDR) genes on osteoporosis. A total of 472 elders were included. Seven variants (TNF-α: rs1799964, rs1800629, rs3093662; VDR: rs7975232, rs1544410, rs2239185, rs3782905) were genotyped. Bone mineral densities of the lumbar spine, femoral neck, and total hip were measured by dual-energy X-ray absorptiometry. Predictive models’ ability to discriminate osteoporosis status was evaluated by areas under the receiver operating characteristics (AUROC) curve. After multivariable adjustment, significant interactions of TNF-α rs1800629 and VDR rs3782905 were observed on overall and lumbar spine osteoporosis. In elderly women, we found that those carrying the CG/CC genotype of VDR rs3782905 were significantly associated with increased odds of overall osteoporosis compared with those carrying the GG genotype of VDR rs3782905 among those carrying TNF-α rs1800629 GG genotype. The adjusted odds ratios (ORs) for VDR rs3782905 CG/CC genotype in elderly women carrying TNF-α rs1800629 AG/AA and GG genotypes were 0.1 (0.01, 0.98) and 3.54 (1.51, 8.30), respectively. We observed significant differences in AUROCs between the model with traditional covariates plus variants and their interaction term and the model with traditional covariates only (AUROCs: 0.77 and 0.81; p = 0.028). Although the sample size of this study may have been relatively small, our results suggest that the interaction of the CG/CC genotype of VDR rs3782905 with TNF-α rs1800629 GG genotype was associated with increased odds of overall and lumbar spine osteoporosis in elderly women.

Klíčová slova:

Cytokines – Elderly – Inflammation – Osteoporosis – Physical activity – Variant genotypes


1. McCormick RK. Osteoporosis: integrating biomarkers and other diagnostic correlates into the management of bone fragility. Alternative medicine review: a journal of clinical therapeutic. 2007;12(2):113–45. Epub 2007/07/03. 17604458.

2. Bruunsgaard H, Ladelund S, Pedersen AN, Schroll M, Jorgensen T, Pedersen BK. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clinical and experimental immunology. 2003;132(1):24–31. doi: 10.1046/j.1365-2249.2003.02137.x 12653832.

3. Manolagas SC. The role of IL-6 type cytokines and their receptors in bone. Annals of the New York Academy of Sciences. 1998;840:194–204. doi: 10.1111/j.1749-6632.1998.tb09563.x 9629251.

4. Richards C, Gauldie J. Role of cytokines in acute-phase response. Cambridge, MA: Blackwell Science; 1995. 253–69 p.

5. Pacifici R. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 1996;11(8):1043–51. doi: 10.1002/jbmr.5650110802 8854239.

6. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocrine reviews. 2000;21(2):115–37. doi: 10.1210/edrv.21.2.0395 10782361.

7. Riggs BL, Khosla S, Melton LJ 3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocrine reviews. 2002;23(3):279–302. doi: 10.1210/edrv.23.3.0465 12050121.

8. Clowes JA, Riggs BL, Khosla S. The role of the immune system in the pathophysiology of osteoporosis. Immunological reviews. 2005;208:207–27. doi: 10.1111/j.0105-2896.2005.00334.x 16313351.

9. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. The New England journal of medicine. 1995;332(5):305–11. doi: 10.1056/NEJM199502023320506 7816067.

10. Manolagas SC. Role of cytokines in bone resorption. Bone. 1995;17(2 Suppl):63S–7S. doi: 10.1016/8756-3282(95)00180-l 8579900.

11. Caetano-Lopes J, Canhao H, Fonseca JE. Osteoimmunology—the hidden immune regulation of bone. Autoimmunity reviews. 2009;8(3):250–5. doi: 10.1016/j.autrev.2008.07.038 18722561.

12. Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, et al. Cytokine gene polymorphism in human disease: on-line databases. Genes and immunity. 1999;1(1):3–19. Epub 2001/02/24. doi: 10.1038/sj.gene.6363645 11197303.

13. Lio D, Scola L, Crivello A, Colonna-Romano G, Candore G, Bonafe M, et al. Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10–1082 promoter SNP and its interaction with TNF-alpha -308 promoter SNP. Journal of medical genetics. 2003;40(4):296–9. Epub 2003/04/05. doi: 10.1136/jmg.40.4.296 12676903

14. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(7):3195–9. doi: 10.1073/pnas.94.7.3195 9096369.

15. Fairbrother UL, Tanko LB, Walley AJ, Christiansen C, Froguel P, Blakemore AI. Leptin receptor genotype at Gln223Arg is associated with body composition, BMD, and vertebral fracture in postmenopausal Danish women. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2007;22(4):544–50. doi: 10.1359/jbmr.070114 17243864.

16. Furuta I, Kobayashi N, Fujino T, Kobamatsu Y, Shirogane T, Yaegashi M, et al. Bone mineral density of the lumbar spine is associated with TNF gene polymorphisms in early postmenopausal Japanese women. Calcified tissue international. 2004;74(6):509–15. doi: 10.1007/s00223-003-0105-6 15354858.

17. Ota N, Nakajima T, Ezura Y, Iwasaki H, Suzuki T, Hosoi T, et al. Association of a single nucleotide variant in the human tumour necrosis factor alpha promoter region with decreased bone mineral density. Annals of human biology. 2002;29(5):550–8. doi: 10.1080/03014460210135730 12396374.

18. Ota N, Nakajima T, Nakazawa I, Suzuki T, Hosoi T, Orimo H, et al. A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density. Journal of human genetics. 2001;46(5):267–72. doi: 10.1007/s100380170077 11355017.

19. Garnero P, Borel O, Sornay-Rendu E, Duboeuf F, Jeffery R, Woo P, et al. Association between a functional interleukin-6 gene polymorphism and peak bone mineral density and postmenopausal bone loss in women: the OFELY study. Bone. 2002;31(1):43–50. doi: 10.1016/s8756-3282(02)00810-4 12110411.

20. Lin CC, Li TC, Liu CS, Yang CW, Lin CH, Hsiao JH, et al. Associations of TNF-alpha and IL-6 polymorphisms with osteoporosis through joint effects and interactions with LEPR gene in Taiwan: Taichung Community Health Study for Elders (TCHS-E). Molecular biology reports. 2016;43(10):1179–91. doi: 10.1007/s11033-016-4037-4 27401061.

21. Ota N, Hunt SC, Nakajima T, Suzuki T, Hosoi T, Orimo H, et al. Linkage of human tumor necrosis factor-alpha to human osteoporosis by sib pair analysis. Genes and immunity. 2000;1(4):260–4. doi: 10.1038/sj.gene.6363668 11196702.

22. Bikle DD. Extrarenal Synthesis of 1,25-Dihydroxyvitamin D and Its Health Implications. In: Holick MF, editor. Vitamin D: Physiology, Molecular Biology, and Clinical Applications. Second ed. New York: Humana Press; 2010. p. 277–95.

23. Liu W, Chen Y, Golan MA, Annunziata ML, Du J, Dougherty U, et al. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. The Journal of clinical investigation. 2013;123(9):3983–96. doi: 10.1172/JCI65842 23945234.

24. Choi M, Park H, Cho S, Lee M. Vitamin D3 supplementation modulates inflammatory responses from the muscle damage induced by high-intensity exercise in SD rats. Cytokine. 2013;63(1):27–35. doi: 10.1016/j.cyto.2013.03.018 23669253.

25. Muller K, Haahr PM, Diamant M, Rieneck K, Kharazmi A, Bendtzen K. 1,25-Dihydroxyvitamin D3 inhibits cytokine production by human blood monocytes at the post-transcriptional level. Cytokine. 1992;4(6):506–12. doi: 10.1016/1043-4666(92)90012-g 1337987.

26. Pedeutour F, Merscher S, Durieux E, Montgomery K, Krauter K, Clevy JP, et al. Mapping of the 12q12-q22 region with respect to tumor translocation breakpoints. Genomics. 1994;22(3):512–8. doi: 10.1006/geno.1994.1424 8001964.

27. Menezes RJ, Cheney RT, Husain A, Tretiakova M, Loewen G, Johnson CS, et al. Vitamin D receptor expression in normal, premalignant, and malignant human lung tissue. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2008;17(5):1104–10. doi: 10.1158/1055-9965.EPI-07-2713 18483332.

28. Zhang L, Yin X, Wang J, Xu D, Wang Y, Yang J, et al. Associations between VDR Gene Polymorphisms and Osteoporosis Risk and Bone Mineral Density in Postmenopausal Women: A systematic review and Meta-Analysis. Scientific reports. 2018;8(1):981. doi: 10.1038/s41598-017-18670-7 29343720.

29. Wu FY, Liu CS, Liao LN, Li CI, Lin CH, Yang CW, et al. Vitamin D receptor variability and physical activity are jointly associated with low handgrip strength and osteoporosis in community-dwelling elderly people in Taiwan: the Taichung Community Health Study for Elders (TCHS-E). Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2014;25(7):1917–29. doi: 10.1007/s00198-014-2691-8 24682357.

30. Liu YZ, Liu YJ, Recker RR, Deng HW. Molecular studies of identification of genes for osteoporosis: the 2002 update. The Journal of endocrinology. 2003;177(2):147–96. doi: 10.1677/joe.0.1770147 12740006.

31. Ferrari SL, Rizzoli R. Gene variants for osteoporosis and their pleiotropic effects in aging. Molecular aspects of medicine. 2005;26(3):145–67. doi: 10.1016/j.mam.2005.01.002 15811432.

32. Melhus H, Kindmark A, Amer S, Wilen B, Lindh E, Ljunghall S. Vitamin D receptor genotypes in osteoporosis. Lancet. 1994;344(8927):949–50. doi: 10.1016/s0140-6736(94)92297-7 7934357.

33. Spector TD, Keen RW, Arden NK, Morrison NA, Major PJ, Nguyen TV, et al. Influence of vitamin D receptor genotype on bone mineral density in postmenopausal women: a twin study in Britain. Bmj. 1995;310(6991):1357–60. doi: 10.1136/bmj.310.6991.1357 7787536.

34. Mencej-Bedrac S, Prezelj J, Kocjan T, Teskac K, Ostanek B, Smelcer M, et al. The combinations of polymorphisms in vitamin D receptor, osteoprotegerin and tumour necrosis factor superfamily member 11 genes are associated with bone mineral density. Journal of molecular endocrinology. 2009;42(3):239–47. doi: 10.1677/JME-08-0108 19131500.

35. Lin CC, Li CI, Chang CK, Liu CS, Lin CH, Meng NH, et al. Reduced health-related quality of life in elders with frailty: a cross-sectional study of community-dwelling elders in Taiwan. PloS one. 2011;6(7):e21841. doi: 10.1371/journal.pone.0021841 21747961.

36. Kanis JA. Assessment of osteoporosis at the primary health-care level. University of Sheffield: World Health Organization Collaborating Centre for Metabolic Bone Diseases; 2007.

37. Kotrych D, Dziedziejko V, Safranow K, Sroczynski T, Staniszewska M, Juzyszyn Z, et al. TNF-alpha and IL10 gene polymorphisms in women with postmenopausal osteoporosis. European journal of obstetrics, gynecology, and reproductive biology. 2016;199:92–5. doi: 10.1016/j.ejogrb.2016.01.037 26914399.

38. Boron D, Kaminski A, Kotrych D, Bogacz A, Uzar I, Mrozikiewicz PM, et al. Polymorphism of vitamin D3 receptor and its relation to mineral bone density in perimenopausal women. Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2015;26(3):1045–52. doi: 10.1007/s00198-014-2947-3 25407264.

39. Sassi R, Sahli H, Souissi C, Sellami S, Ben Ammar El Gaaied A. Polymorphisms in VDR gene in Tunisian postmenopausal women are associated with osteopenia phenotype. Climacteric: the journal of the International Menopause Society. 2015;18(4):624–30. doi: 10.3109/13697137.2015.1007123 25603555.

40. Qin G, Dong Z, Zeng P, Liu M, Liao X. Association of vitamin D receptor BsmI gene polymorphism with risk of osteoporosis: a meta-analysis of 41 studies. Molecular biology reports. 2013;40(1):497–506. doi: 10.1007/s11033-012-2086-x 23054016.

41. Jia F, Sun RF, Li QH, Wang DX, Zhao F, Li JM, et al. Vitamin D receptor BsmI polymorphism and osteoporosis risk: a meta-analysis from 26 studies. Genetic testing and molecular biomarkers. 2013;17(1):30–4. doi: 10.1089/gtmb.2012.0267 23134477.

42. Zhao B, Zhang W, Du S, Zhou Z. Vitamin D receptor BsmI polymorphism and osteoporosis risk in post-menopausal women. Archives of medical science: AMS. 2016;12(1):25–30. doi: 10.5114/aoms.2016.57475 26925115.

43. Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory mediators in the elderly. Experimental gerontology. 2004;39(5):687–99. doi: 10.1016/j.exger.2004.01.009 15130663.

44. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. The New England journal of medicine. 1999;340(6):448–54. doi: 10.1056/NEJM199902113400607 9971870.

45. Ren H, Sun R, Wang J. Relationship of melatonin level, oxidative stress and inflammatory status with osteoporosis in maintenance hemodialysis of chronic renal failure. Experimental and therapeutic medicine. 2018;15(6):5183–8. doi: 10.3892/etm.2018.5857 29904403.

46. Li CI, Li TC, Liao LN, Liu CS, Yang CW, Lin CH, et al. Joint effect of gene-physical activity and the interactions among CRP, TNF-alpha, and LTA polymorphisms on serum CRP, TNF-alpha levels, and handgrip strength in community-dwelling elders in Taiwan—TCHS-E. Age. 2016;38(2):46. doi: 10.1007/s11357-016-9909-y 27056089.

47. Kaplan V, Angus DC, Griffin MF, Clermont G, Scott Watson R, Linde-Zwirble WT. Hospitalized community-acquired pneumonia in the elderly: age- and sex-related patterns of care and outcome in the United States. American journal of respiratory and critical care medicine. 2002;165(6):766–72. doi: 10.1164/ajrccm.165.6.2103038 11897642.

48. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. Jama. 2003;289(2):179–86. doi: 10.1001/jama.289.2.179 12517228.

49. Bikle D. Nonclassic actions of vitamin D. The Journal of clinical endocrinology and metabolism. 2009;94(1):26–34. doi: 10.1210/jc.2008-1454 18854395.

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