Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 12, December, p. 1717–1722

doi: 10.17219/acem/75689

Publication type: original article

Language: English

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ALOX12 gene polymorphisms and serum selenium status in elderly osteoporotic patients

Atiyeh Al-e-Ahmad1,2,A,B,C,D,F, Hadi Parsian3,A,B,C,D,E,F, Mojtaba Fathi2,A,B,C,D,E,F, Soghrat Faghihzadeh4,A,C,E,F, Seyed Reza Hosseini5,A,B,F, Haji Ghorban Nooreddini6,A,B,F, Abbas Mosapour7,B,F

1 Mobility Impairment Research Center, Health Research Institute, Babol University of Medical Sciences, Iran

2 Department of Biochemistry and Nutrition, Faculty of Medicine, Zanjan University of Medical Sciences, Iran

3 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Iran

4 Department of Biostatistics and Epidemiology, Faculty of Medicine, Zanjan University of Medical Sciences, Iran

5 Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Iran

6 Department of Internal Medicine, Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Iran

7 Department of Biochemistry, School of Medicine, Babol University of Medical Sciences, Iran


Background. Osteoporosis is a systemic bone disease which leads to a reduction in bone mass. Many studies have shown that up to 80% of bone mineral density (BMD) variations are attributed to genetic factors. Arachidonate 12-lipoxygenase enzyme, encoded by the ALOX12 gene, produces lipid peroxides as reactive oxygen species (ROS), leading to oxidative stress and the development of osteoporosis. Selenium (Se) is incorporated into selenoproteins, which may reduce the risk of osteoporosis.
Objectives. We aimed to investigate the association of 2 ALOX12 single nucleotide polymorphisms (SNPs) and serum Se level with lumbar spine and femoral neck BMD among elderly individuals living in Amirkola, Iran.
Material and Methods. The study consisted of 180 individuals aged ≥60 years (90 healthy and 90 osteoporotic patients). We examined the effect of 2 ALOX12 SNPs (rs2292350 and rs9897850), using the polymerase chain reaction – restriction fragment length polymorphism (PCR–RFLP) on both BMD regions measured by dual energy X-ray absorptiometry (DXA). Serum Se level was measured using an atomic absorption spectrophotometer PGG990 AAS (PG Instruments Ltd., Luterworth, USA).
Results. The rs2292350 SNP showed a significant association with femoral neck BMD (p = 0.04). Moreover, in terms of serum Se level, a significant difference was found between the patient group (57.58 ±25.54 μg/L) and the control group (81.09 ±25.58 μg/L) (p < 0.001). In addition, individuals with higher serum Se levels also had higher BMD of the lumbar spine (r2 = 0.392; p < 0.001) and the femoral neck (r2 = 0.478; p < 0.001).
Conclusion. The results suggested that genetic variation in ALOX12 might influence BMD variations in our recruited participants. As for the patients with lower serum Se levels, it was observed that serum Se deficiency was accompanied by some ALOX12 variation, contributing to the development of osteoporosis.

Key words

osteoporosis, single nucleotide polymorphism, bone mineral density, ALOX12, selenium

References (40)

  1. Ichikawa S, Koller DL, Johnson ML, et al. Human ALOX12, but not ALOX15, is associated with BMD in white men and women. J Bone Miner Res. 2006;21:556–564.
  2. Cooper C, Campion G, Melton III LJ. Hip fractures in the elderly: A worldwide projection. Osteoporos Int. 1992;2:285–289.
  3. Rahnavard Z, Zolfaghari M, Hossein-Nezad A, Vahid Dastgerdi M. The incidence of osteoporotic Hip fracture: Iranian Multicenter Osteoporosis Study (IMOS). Res J Biol Sci. 2009;4:171–173.
  4. Harsløf T, Husted LB, Nyegaard M, et al. Polymorphisms in the ALOX12 gene and osteoporosis. Osteoporos Int. 2011;22:2249–2259.
  5. Xiao WJ, Ke YH, He JW, et al. Polymorphisms in the human ALOX12 and ALOX15 genes are associated with peak bone mineral density in Chinese nuclear families. Osteoporos Int. 2012;23:1889–1897.
  6. Brown LB, Streeten EA, Shapiro JR, et al. Genetic and environmental influences on bone mineral density in pre-and post-menopausal women. Osteoporos Int. 2005;16:1849–1856.
  7. Mullin B, Spector T, Curtis C, et al. Polymorphisms in ALOX12, but not ALOX15, are significantly associated with BMD in postmenopausal women. Calcif Tissue Int. 2007;81:10–17.
  8. Devoto M, Shimoya K, Caminis J, et al. First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q. Eur J Hum Genet. 1998;6:151–157.
  9. Deng HW, Xu FH, Huang QY, et al. A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait loci for osteoporosis. J Clin Endocrinol Metab. 2002;87:5151–5159.
  10. Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME. Playing with bone and fat. J Cell Biochem. 2006;98:251–266.
  11. Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL. Divergent effects of selective peroxisome proliferator-activated receptor-γ 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology. 2002;143:2376–2384.
  12. Khan E, Abu-Amer Y. Activation of peroxisome proliferator–activated receptor-γ inhibits differentiation of preosteoblasts. J Lab Clin Med. 2003;142:29–34.
  13. Akune T, Ohba S, Kamekura S, et al. PPAR-γ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004;113:846.
  14. Kawaguchi H, Akune T, Yamaguchi M, et al. Distinct effects of PPAR-γ insufficiency on bone marrow cells, osteoblasts, and osteoclastic cells. J Bone Miner Metab. 2005;23:275–279.
  15. Xiong DH, Shen H, Zhao LJ, et al. Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high‐density single‐nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene–gene interaction. J Bone Miner Res. 2006;21:1678–1695.
  16. Ebert R, Jakob F. Selenium deficiency as a putative risk factor for osteoporosis. Int Congr Ser. 2007;1297:158–164.
  17. Müller C, Wingler K, Brigelius-Flohe R. 3’UTRs of glutathione peroxidases differentially affect selenium-dependent mRNA stability and selenocysteine incorporation efficiency. Biol Chem. 2003;384:11–18.
  18. Liu H, Bian W, Liu S, Huang K. Selenium protects bone marrow stromal cells against hydrogen peroxide-induced inhibition of osteoblastic differentiation by suppressing oxidative stress and ERK signaling pathway. Biol Trace Elem Res. 2012;150:441–450.
  19. Manolagas SC. From estrogen-centric to aging and oxidative stress: A revised perspective of the pathogenesis of osteoporosis. Endocr Rev. 2010;31:266–300.
  20. Mackinnon E, Rao A, Josse R, Rao L. Supplementation with the antioxidant lycopene significantly decreases oxidative stress parameters and the bone resorption marker N-telopeptide of type I collagen in postmenopausal women. Osteoporos Int. 2011;22:1091–1101.
  21. Ruiz-Ramos M, Vargas LA, Van der Goes TF, Cervantes-Sandoval A, Mendoza-Nunez V. Supplementation of ascorbic acid and alpha-tocopherol is useful to preventing bone loss linked to oxidative stress in elderly. J Nutr. 2010;14:467–472.
  22. Zhang J, Munger RG, West NA, Cutler DR, Wengreen HJ, Corcoran CD. Antioxidant intake and risk of osteoporotic hip fracture in Utah: An effect modified by smoking status. Am J Epidemiol. 2006;163:9–17.
  23. Moreno‐Reyes R, Egrise D, Neve J, Pasteels JL, Schoutens A. Selenium deficiency‐induced growth retardation is associated with an impaired bone metabolism and osteopenia. J Bone Miner Res. 2001;16:1556–1563.
  24. Hosseini SR, Cumming RG, Kheirkhah F, et al. Cohort profile: The Amirkola Health and Ageing Project (AHAP). Int J Epidemiol. 2014;43:1393–1400.
  25. WHO. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO study group. World Health Organ Tech Rep Ser. 1994;843:1–129.
  26. Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol. 2009;169:505–514.
  27. Gaunt TR, Rodríguez S, Day IN. Cubic exact solutions for the estimation of pairwise haplotype frequencies: Implications for linkage disequilibrium analyses and a web tool ’CubeX’. BMC Bioinformatics. 2007;8:428.
  28. Khoury MJ, Beaty TH, Cohen BH. Fundamentals of Genetic Epidemiology. New York, NY: Oxford University Press; 1993.
  29. Hosking L, Lumsden S, Lewis K, et al. Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur J Hum Genet. 2004;12: 395–399.
  30. Bai XC, Lu D, Bai J, et al. Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-κB. Biochem Biophys Res Commun. 2004;314:197–207.
  31. Mody N, Parhami F, Sarafian TA, Demer LL. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med. 2001;31:509–519.
  32. Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL. Increased lipid oxidation causes oxidative stress, increased peroxisome proliferator-activated receptor-γ expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem. 2009;284:27438–27448.
  33. Kim WK, Meliton V, Bourquard N, Hahn TJ, Parhami F. Hedgehog signaling and osteogenic differentiation in multipotent bone marrow stromal cells are inhibited by oxidative stress. J Cell Biochem. 2010;111:1199–1209.
  34. Basu S, Michaëlsson K, Olofsson H, Johansson S, Melhus H. Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun. 2001;288:275–279.
  35. Zeng H, Cao JJ, Combs GF. Selenium in bone health: Roles in antioxidant protection and cell proliferation. Nutrients. 2013;5:97–110.
  36. Chen CJ, Huang HS, Lin SB, Chang WC. Regulation of cyclooxygenase and 12-lipoxygenase catalysis by phospholipid hydroperoxide glutathione peroxidase in A431 cells. Prostaglandins Leukot Essent Fatty Acids. 2000;62:261–268.
  37. Chen CJ, Huang HS, Chang WC. Inhibition of arachidonate metabolism in human epidermoid carcinoma a431 cells overexpressing phospholipid hydroperoxide glutathione peroxidase. J Biomed Sci. 2002;9:453–459.
  38. Chen CJ, Huang HS, Chang WC. Depletion of phospholipid hydroperoxide glutathione peroxidase up-regulates arachidonate metabolism by 12 (S)-lipoxygenase and cyclooxygenase 1 in human epidermoid carcinoma A431 cells. FASEB. 2003;17:1694–1696.
  39. Odabasi E, Turan M, Aydin A, Akay C, Kutlu M. Magnesium, zinc, copper, manganese, and selenium levels in postmenopausal women with osteoporosis. Can magnesium play a key role in osteoporosis? Ann Acad Med Singapore. 2008;37:564–567.
  40. Arikan DC, Coskun A, Ozer A, Kilinc M, Atalay F, Arikan T. Plasma selenium, zinc, copper and lipid levels in postmenopausal Turkish women and their relation with osteoporosis. Biol Trace Elem Res. 2011; 144:407–417.