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Associations of TNF-α and IL-6 polymorphisms with osteoporosis through joint effects and interactions with LEPR gene in Taiwan: Taichung Community Health Study for Elders (TCHS-E)

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Abstract

Osteoporosis (OST) is a complex multifactorial disease considered to result from interactions of multiple gene and environmental factors. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 are pleiotropic cytokines essential for bone remodeling; and hormone leptin has immunomodulatory effects that stimulate the synthesis of IL-6 and TNF-α. Leptin is involved in the modulation of bone growth and turnover; and its actions are bound by leptin receptor (LEPR). Prior studies evaluated the effects of TNF-α, IL-6, and LEPR gene polymorphisms separately on bone mineral densities (BMD) or OST. In this study, we assessed the roles of TNF-α and IL-6 gene polymorphisms in OST through joint effects and interactions with LEPR gene. We also evaluated possible joint effects and interactions between these polymorphisms and physical activity. Ten tag-SNPs (rs1799964, rs1800629, rs3093662 in TNF-α; rs1880243, rs1800796, rs1554606 in IL-6; and rs1751492, rs8179183, rs1805096, rs1892534 in LEPR) were used to genotype 103 OST cases and 369 controls. BMD of lumbar spine (LS), femoral neck (FN), and total hip (TH) were measured by dual-energy X-ray absorptiometry. Our data showed that TNF-α and IL-6 polymorphisms were associated with overall and site-specific OST in both sexes, and that these associations were dependent on rs1805096 and rs1892534 genotypes of LEPR. In men, LEPR A-G-G-G haplotype was associated with FN OST (OR 4.65, 95 % CI 1.61–13.40, p = 0.004). Genotype AA/AG of LEPR rs1751492 was associated with overall and FN OST in women without physical activity, but not in women with physical activity (p < 0.05 for interaction between physical activity and LEPR rs1751492). In men, we detected significant interactions of IL-6 rs1800796 with LEPR rs1805096 and rs1892534 for FN and TH OST (all p < 0.05). Our data indicate that LEPR gene may play joint and interactive roles with TNF-α and IL-6 genes and physical inactivity in development of OST. Haplotype analyses revealed that the correlations tended to be prominent in men with FN OST.

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Acknowledgments

This study was supported by grants from the National Health Research Institutes of Taiwan (NHRI-EX98-9838PI), China Medical University (CMU103-S-02), and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105-TDU-B-212-133019).

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    Authors and Affiliations

    1. School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan

      Cheng-Chieh Lin, Chiu-Shong Liu, Chih-Hsueh Lin, Nai-Hsin Meng, Wen-Yuan Lin, Li-Na Liao & Chia-Ing Li

    2. Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan

      Cheng-Chieh Lin, Chiu-Shong Liu, Chih-Hsueh Lin & Wen-Yuan Lin

    3. Graduate Institute of Biostatistics, College of Public Health, China Medical University, Taichung, Taiwan

      Tsai-Chung Li

    4. Department of Healthcare Administration, College of Medical and Health Sciences, Asia University, Taichung, Taiwan

      Tsai-Chung Li

    5. Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

      Chuan-Wei Yang & Chia-Ing Li

    6. Ph.D. Program for Aging, College of Medicine, China Medical University, Taichung, Taiwan

      Chuan-Wei Yang

    7. Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan

      Jen-Hao Hsiao

    8. Department of Physical Medicine and Rehabilitation, China Medical University Hospital, Taichung, Taiwan

      Nai-Hsin Meng

    9. Department of Public Health, College of Public Health, China Medical University, No. 91 Hsueh-Shih Road, 40402, Taichung, Taiwan

      Fang-Yang Wu

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    Lin, CC., Li, TC., Liu, CS. et al. Associations of TNF-α and IL-6 polymorphisms with osteoporosis through joint effects and interactions with LEPR gene in Taiwan: Taichung Community Health Study for Elders (TCHS-E). Mol Biol Rep 43, 1179–1191 (2016). https://doi.org/10.1007/s11033-016-4037-4

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