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Causal relationship between the AHSG gene and BMD through fetuin-A and BMI: multiple mediation analysis

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Abstract

Summary

Using mediation analysis, a causal relationship between the AHSG gene and bone mineral density (BMD) through fetuin-A and body mass index (BMI) mediators was suggested.

Introduction

Fetuin-A, a multifunctional protein of hepatic origin, is associated with bone mineral density. It is unclear if this association is causal. This study aimed at clarification of this issue.

Methods

A cross-sectional study was conducted among 1,741 healthy workers from the Electricity Generating Authority of Thailand (EGAT) cohort. The alpha-2-Heremans–Schmid glycoprotein (AHSG) rs2248690 gene was genotyped. Three mediation models were constructed using seemingly unrelated regression analysis. First, the ln[fetuin-A] group was regressed on the AHSG gene. Second, the BMI group was regressed on the AHSG gene and the ln[fetuin-A] group. Finally, the BMD model was constructed by fitting BMD on two mediators (ln[fetuin-A] and BMI) and the independent AHSG variable. All three analyses were adjusted for confounders.

Results

The prevalence of the minor T allele for the AHSG locus was 15.2 %. The AHSG locus was highly related to serum fetuin-A levels (P < 0.001). Multiple mediation analyses showed that AHSG was significantly associated with BMD through the ln[fetuin-A] and BMI pathway, with beta coefficients of 0.0060 (95 % CI 0.0038, 0.0083) and 0.0030 (95 % CI 0.0020, 0.0045) at the total hip and lumbar spine, respectively. About 27.3 and 26.0 % of total genetic effects on hip and spine BMD, respectively, were explained by the mediation effects of fetuin-A and BMI.

Conclusions

Our study suggested evidence of a causal relationship between the AHSG gene and BMD through fetuin-A and BMI mediators.

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References

  1. Rasul S, Wagner L, Kautzky-Willer A (2012) Fetuin-A and angiopoietins in obesity and type 2 diabetes mellitus. Endocrine 42(3):496–505. doi:10.1007/s12020-012-9754-4

    Article  CAS  PubMed  Google Scholar 

  2. Ix JH, Wassel CL, Bauer DC, Toroian D, Tylavsky FA, Cauley JA, Harris TB, Price PA, Cummings SR, Shlipak MG, Health ABCS (2009) Fetuin-A and BMD in older persons: the Health Aging and Body Composition (Health ABC) study. J Bone Miner Res 24(3):514–521. doi:10.1359/jbmr.081017

    Article  PubMed Central  PubMed  Google Scholar 

  3. Chailurkit L, Kruavit A, Rajatanavin R, Ongphiphadhanakul B (2011) The relationship of fetuin-A and lactoferrin with bone mass in elderly women. Osteoporos Int 22(7):2159–2164. doi:10.1007/s00198-010-1439-3

    Article  CAS  PubMed  Google Scholar 

  4. Fisher E, Stefan N, Saar K, Drogan D, Schulze MB, Fritsche A, Joost HG, Haring HU, Hubner N, Boeing H, Weikert C (2009) Association of AHSG gene polymorphisms with fetuin-A plasma levels and cardiovascular diseases in the EPIC-Potsdam study. Circ Cardiovasc Genet 2(6):607–613. doi:10.1161/CIRCGENETICS.109.870410

    Article  CAS  PubMed  Google Scholar 

  5. Osawa M, Tian W, Horiuchi H, Kaneko M, Umetsu K (2005) Association of alpha2-HS glycoprotein (AHSG, fetuin-A) polymorphism with AHSG and phosphate serum levels. Hum Genet 116(3):146–151. doi:10.1007/s00439-004-1222-7

    Article  CAS  PubMed  Google Scholar 

  6. Thakkinstian A, Chailurkit L, Warodomwichit D, Ratanachaiwong W, Yamwong S, Chanprasertyothin S, Attia J, Sritara P, Ongphiphadhanakul B (2014) Causal relationship between body mass index and fetuin-a level in the Asian population: a bidirectional Mendelian randomisation study. Clin Endocrinol (Oxf). doi:10.1111/cen.12303

    Google Scholar 

  7. Beck TJ, Petit MA, Wu G, LeBoff MS, Cauley JA, Chen Z (2009) Does obesity really make the femur stronger? BMD, geometry, and fracture incidence in the Women’s Health Initiative-observational study. J Bone Miner Res 24(8):1369–1379. doi:10.1359/jbmr.090307

    Article  PubMed Central  PubMed  Google Scholar 

  8. De Laet C, Kanis JA, Oden A, Johanson H, Johnell O, Delmas P, Eisman JA, Kroger H, Fujiwara S, Garnero P, McCloskey EV, Mellstrom D, Melton LJ 3rd, Meunier PJ, Pols HA, Reeve J, Silman A, Tenenhouse A (2005) Body mass index as a predictor of fracture risk: a meta-analysis. Osteoporos Int 16(11):1330–1338. doi:10.1007/s00198-005-1863-y

    Article  PubMed  Google Scholar 

  9. Johansson H, Kanis JA, Oden A, McCloskey E, Chapurlat RD, Christiansen C, Cummings SR, Diez-Perez A, Eisman JA, Fujiwara S, Gluer CC, Goltzman D, Hans D, Khaw KT, Krieg MA, Kroger H, Lacroix AZ, Lau E, Leslie WD, Mellstrom D, Melton LJ 3rd, O’Neill TW, Pasco JA, Prior JC, Reid DM, Rivadeneira F, van Staa T, Yoshimura N, Zillikens MC (2013) A meta-analysis of the association of fracture risk and body mass index in women. J Bone Miner Res. doi:10.1002/jbmr.2017

    Google Scholar 

  10. Vathesatogkit P, Woodward M, Tanomsup S, Ratanachaiwong W, Vanavanan S, Yamwong S, Sritara P (2012) Cohort profile: the electricity generating authority of Thailand study. Int J Epidemiol 41(2):359–365. doi:10.1093/ije/dyq218

    Article  PubMed  Google Scholar 

  11. Sritara C, Ongphiphadhanakul B, Chailurkit L, Yamwong S, Ratanachaiwong W, Sritara P (2013) Serum uric acid levels in relation to bone-related phenotypes in men and women. J Clin Densitom 16(3):336–340. doi:10.1016/j.jocd.2012.05.008

    Article  PubMed  Google Scholar 

  12. Baim S, Binkley N, Bilezikian JP, Kendler DL, Hans DB, Lewiecki EM, Silverman S (2008) Official positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom 11(1):75–91

    Article  PubMed  Google Scholar 

  13. WHO Global Physical Activity Questionnaire and Analysis Guide. World Health Organization. http://www.who.int/chp/steps/STEPS_Instrument_v2.1.pdf. Accessed 7 Jun 2013

  14. Armstrong T, Bull FC (2006) Development of the World Health Organization Global Physical Activity Questionnaire (GPAQ). J Pub Health 14:66–70

    Article  Google Scholar 

  15. Imai K, Keele L, Tingley D (2010) A general approach to causal mediation analysis. Psychol Methods 15(4):309–334. doi:10.1037/a0020761

    Article  PubMed  Google Scholar 

  16. Preacher KJ, Hayes AF (2008) Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 40(3):879–891

    Article  PubMed  Google Scholar 

  17. Bruin J (2006) Newtest: command to compute new test. UCLA: Statistical Consulting Group. http://www.ats.ucla.edu/stat/stata/ado/analysis/. Accessed 21 Dec 2012

  18. Wang W, Albert JM (2012) Estimation of mediation effects for zero-inflated regression models. Stat Med 31(26):3118–3132. doi:10.1002/sim.5380

    Article  PubMed Central  PubMed  Google Scholar 

  19. Taylor AB, MacKinnon DP, Tein J-Y (2008) Tests of the three-path mediated effect. Organ Res Methods 11(2):241–269

    Article  Google Scholar 

  20. MacKinnon DP, Lockwood CM, Hoffman JM, West SG, Sheets V (2002) A comparison of methods to test mediation and other intervening variable effects. Psychol Methods 7(1):83–104

    Article  PubMed Central  PubMed  Google Scholar 

  21. Preacher KJ, Hayes AF (2004) SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behav Res Methods Instrum Comput 36(4):717–731

    Article  PubMed  Google Scholar 

  22. Imai K, Yamamoto T (2013) Identification and sensitivity analysis for multiple causal mechanisms: revisiting evidence from framing experiments. Polit Anal 21(2):141–171. doi:10.1093/pan/mps040

    Article  Google Scholar 

  23. Tingley D, Yamamoto T, Hirose K, Keele L, Imai K (2014) mediation: R package for causal mediation analysis. J Stat Softw (in press)

  24. Verduijn M, Prein RA, Stenvinkel P, Carrero JJ, le Cessie S, Witasp A, Nordfors L, Krediet RT, Boeschoten EW, Dekker FW (2011) Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach. Nephrol Dial Transplant 26(1):239–245. doi:10.1093/ndt/gfq402

    Article  CAS  PubMed  Google Scholar 

  25. Weikert C, Stefan N, Schulze MB, Pischon T, Berger K, Joost HG, Haring HU, Boeing H, Fritsche A (2008) Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation 118(24):2555–2562. doi:10.1161/CIRCULATIONAHA.108.814418

    Article  CAS  PubMed  Google Scholar 

  26. Smith GD, Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 32(1):1–22

    Article  PubMed  Google Scholar 

  27. Kenny DA (2012) Mediation. http://davidakenny.net/cm/mediate.htm. Accessed 9 Jan 2014

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Acknowledgments

This study was supported by the National Research University Initiative and the Research Promotion in Higher Education Project, Office of the Higher Education Commission; and the Thailand Research Fund. We thank Berli Jucker Public Co. (Thailand) Ltd. for providing a DXA machine and technical support. We would like to thank Ms. Nisakorn Thongmung for her enthusiastic and efficient collaboration.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Diagnostic and Therapeutic Radiology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    C. Sritara

  2. Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand

    A. Thakkinstian

  3. Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    B. Ongphiphadhanakul, L. Chailurkit, P. Vathesatogkit & P. Sritara

  4. Office of Research Academic Affairs and Innovation, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    S. Chanprasertyothin

  5. Medical and Health Office, Electricity Generating Authority of Thailand, Nonthaburi, Thailand

    W. Ratanachaiwong

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  1. C. Sritara
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Correspondence to A. Thakkinstian.

Appendix

Appendix

Percent total mediation effects mediated by me1, me2, and me1me2

  1. a.

    By me1

    $$ \begin{array}{c}\mathrm{Total}\kern2.77695pt \mathrm{effects}={\mathrm{me}}_1+{\mathrm{me}}_2+{\mathrm{me}}_1{\mathrm{me}}_2\\ {}\%\kern3pt {\mathrm{me}}_1=\frac{{\mathrm{me}}_1}{\mathrm{total}\kern3pt \mathrm{effects}}\times 100\end{array} $$
  2. b.

    By me2

    $$ \%{\kern3pt \mathrm{me}}_2=\frac{{\mathrm{me}}_2}{\mathrm{total}\kern2.77695pt \mathrm{effects}}\times 100 $$
  3. c.

    By me1me2

    $$ \%{\kern3pt \mathrm{me}}_1{\mathrm{me}}_2=\frac{{\mathrm{me}}_1{\mathrm{me}}_2}{\mathrm{total}\kern2.77695pt \mathrm{effects}}\times 100 $$

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Sritara, C., Thakkinstian, A., Ongphiphadhanakul, B. et al. Causal relationship between the AHSG gene and BMD through fetuin-A and BMI: multiple mediation analysis. Osteoporos Int 25, 1555–1562 (2014). https://doi.org/10.1007/s00198-014-2634-4

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  • DOI: https://doi.org/10.1007/s00198-014-2634-4

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