title: 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).
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.
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.|Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biostatistics, College of Public Health, China Medical University, Taichung, Taiwan.|Department of Healthcare Administration, College of Medical and Health Sciences, Asia University, Taichung, Taiwan.
authors.forename: Tsai-Chung
authors.initials: TC
authors.lastname: Li
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.|Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chiu-Shong
authors.initials: CS
authors.lastname: Liu
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.|Ph.D. Program for Aging, College of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Chuan-Wei
authors.initials: CW
authors.lastname: Yang
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.|Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chih-Hsueh
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jen-Hao
authors.initials: JH
authors.lastname: Hsiao
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.|Department of Physical Medicine and Rehabilitation, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Nai-Hsin
authors.initials: NH
authors.lastname: Meng
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.|Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Lin
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan. lina7122@gmail.com.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Liao
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan. a6446@mail.cmuh.org.tw.|Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. a6446@mail.cmuh.org.tw.
authors.forename: Chia-Ing
authors.initials: CI
authors.lastname: Li
authors.affiliation: Department of Public Health, College of Public Health, China Medical University, No. 91 Hsueh-Shih Road, 40402, Taichung, Taiwan. fywu@mail.cmu.edu.tw.
authors.forename: Fang-Yang
authors.initials: FY
authors.lastname: Wu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D015519:Bone Density; D015444:Exercise; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D010024:Osteoporosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054411:Receptors, Leptin / Q000235:genetics*; D013624:Taiwan; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C515448:LEPR protein, human; D054411:Receptors, Leptin; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: Gene; Interaction; Joint effect; Osteoporosis; SNP