Skip to main content

Advertisement

SpringerLink
Log in

No causal effect of serum urate on bone-related outcomes among a population of postmenopausal women and elderly men of Chinese Han ethnicity—a Mendelian randomization study

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

We conducted a Mendelian randomization analysis to assess the effect of serum uric acid on bone-related outcomes using a weighted urate transporter genetic risk score as the instrumental variable. The results showed no significance. Our study identified no evidence of a causal role between uric acid and bone-related outcomes.

Introduction

Observational studies have associated elevated levels of serum uric acid (SUA) with increasing bone mineral density (BMD) and a lowered prevalence of osteoporotic fractures (OFs) in postmenopausal women and elderly men. However, due to unmeasured confounding variables, these observational studies have not provided insight into the causal relationship between SUA and bone-related outcomes. Our aim was to evaluate the effect of SUA on bone-related outcomes using Mendelian randomization.

Methods

We recruited 1322 Chinese Han individuals (214 elderly men and 1108 postmenopausal women) from the Shanghai area in China. Mendelian randomization using a two-stage least-squares regression method was conducted with SUA as the exposure variable, a weighted urate transporter genetic risk score as the instrumental variable, and all-site BMD, bone turnover markers, and levels of 25-hydroxyvitamin D3 [25(OH)D], serum calcium (Ca), serum phosphorus (P), and parathyroid hormone (PTH) as outcome variables.

Results

Strong associations between SUA and bone-related outcomes were observed in an ordinary observational analysis (lumbar spine: beta = 0.122, p < 0.0001; hip: beta = 0.104, p < 0.0001; femoral neck: beta = 0.108, p < 0.0001). However, the Mendelian randomization analysis showed no evidence for a causal association of SUA with BMD (lumbar spine: beta = 0.385, p = 0.257; hip: beta = 0.191, p = 0.499; femoral neck: beta = 0.194, p = 0.533). Similar results were found between SUA and other bone-related phenotypes.

Conclusions

Our study identified no evidence of a causal role between SUA and bone-related outcomes, although strong associations in an observational analysis were observed in a population of postmenopausal women and elderly men.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, Luo SQ (2004) Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 314:197–207

    Article  CAS  PubMed  Google Scholar 

  2. Ha H, Kwak HB, Lee SW, Jin HM, Kim HM, Kim HH, Lee ZH (2004) Reactive oxygen species mediate RANK signaling in osteoclasts. Exp Cell Res 301:119–127

    Article  CAS  PubMed  Google Scholar 

  3. Ostman B, Michaelsson K, Helmersson J, Byberg L, Gedeborg R, Melhus H, Basu S (2009) Oxidative stress and bone mineral density in elderly men: antioxidant activity of alpha-tocopherol. Free Radic Biol Med 47:668–673

    Article  PubMed  Google Scholar 

  4. Bruce N, Ames RC, Elizabeth SH, Paul HC (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 78:6858–6862

    Article  Google Scholar 

  5. Hershfield MS, Roberts LJ, Ganson NJ, Kelly SJ, Santisteban I, Scarlett E, Jaggers D, Sundy JS (2010) Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo. Proc Natl Acad Sci U S A 107:14351–14356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nabipour I, Sambrook PN, Blyth FM et al (2011) Serum uric acid is associated with bone health in older men: a cross-sectional population-based study. J Bone Miner Res 26:955–964

    Article  CAS  PubMed  Google Scholar 

  7. Ahn SH, Lee SH, Kim BJ et al (2013) Higher serum uric acid is associated with higher bone mass, lower bone turnover, and lower prevalence of vertebral fracture in healthy postmenopausal women. Osteoporos Int 24:2961–2970

    Article  CAS  PubMed  Google Scholar 

  8. Makovey J, Macara M, Chen JS, Hayward CS, March L, Seibel MJ, Sambrook PN (2013) Serum uric acid plays a protective role for bone loss in peri- and postmenopausal women: a longitudinal study. Bone 52:400–406

    Article  CAS  PubMed  Google Scholar 

  9. Ishii S, Miyao M, Mizuno Y, Tanaka-Ishikawa M, Akishita M, Ouchi Y (2014) Association between serum uric acid and lumbar spine bone mineral density in peri- and postmenopausal Japanese women. Osteoporos Int 25:1099–1105

    Article  CAS  PubMed  Google Scholar 

  10. Lane NE, Parimi N, Lui L-Y, Wise BL, Yao W, Lay Y-AE, Cawthon PM, Orwoll E (2014) Association of serum uric acid and incident nonspine fractures in elderly men: the Osteoporotic Fractures in Men (MrOS) study. J Bone Miner Res 29:1701–1707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee YJ, Hong JY, Kim SC, Joo JK, Na YJ, Lee KS (2015) The association between oxidative stress and bone mineral density according to menopausal status of Korean women. Obstet Gynecol Sci 58:46–52

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim BJ, Baek S, Ahn SH et al (2014) Higher serum uric acid as a protective factor against incident osteoporotic fractures in Korean men: a longitudinal study using the National Claim Registry. Osteoporos Int 25:1837–1844

    Article  CAS  PubMed  Google Scholar 

  13. Zhang D, Bobulescu IA, Maalouf NM et al (2015) Relationship between serum uric Acid and bone mineral density in the general population and in rats with experimental hyperuricemia. J Bone Miner Res 30:992–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mehta T, Buzkova P, Sarnak MJ, Chonchol M, Cauley JA, Wallace E, Fink HA, Robbins J, Jalal D (2015) Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study. Metabolism 64:438–446

    Article  CAS  PubMed  Google Scholar 

  15. Palmer TM, Lawlor DA, Harbord RM, Sheehan NA, Tobias JH, Timpson NJ, Davey Smith G, Sterne JA (2012) Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res 21:223–242

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kottgen A, Albrecht E, Teumer A et al (2013) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 45:145–154

    Article  PubMed  Google Scholar 

  17. Sulem P, Gudbjartsson DF, Walters GB et al (2011) Identification of low-frequency variants associated with gout and serum uric acid levels. Nat Genet 43:1127–1130

    Article  CAS  PubMed  Google Scholar 

  18. Yang B, Mo Z, Wu C et al (2014) A genome-wide association study identifies common variants influencing serum uric acid concentrations in a Chinese population. BMC Med Genomics 7:10

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pfister R, Barnes D, Luben R, Forouhi NG, Bochud M, Khaw KT, Wareham NJ, Langenberg C (2011) No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomisation approach. Diabetologia 54:2561–2569

    Article  CAS  PubMed  Google Scholar 

  20. Hughes K, Flynn T, de Zoysa J, Dalbeth N, Merriman TR (2014) Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function. Kidney Int 85:344–351

    Article  CAS  PubMed  Google Scholar 

  21. Rasheed H, Hughes K, Flynn TJ, Merriman TR (2014) Mendelian randomization provides no evidence for a causal role of serum urate in increasing serum triglyceride levels. Circ Cardiovasc Genet 7:830–837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Simon KC, Eberly S, Gao X et al (2014) Mendelian randomization of serum urate and Parkinson disease progression. Ann Neurol 76:862–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lu HK, Zhang Z, Ke YH, He JW, Fu WZ, Zhang CQ, Zhang ZL (2012) High prevalence of vitamin D insufficiency in China: relationship with the levels of parathyroid hormone and markers of bone turnover. PLoS One 7:e47264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang H, He JW, Gao G et al (2010) Polymorphisms in the HOXD4 gene are not associated with peak bone mineral density in Chinese nuclear families. Acta Pharmacol Sin 31:977–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kolz M, Johnson T, Sanna S et al (2009) Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet 5, e1000504

    Article  PubMed  PubMed Central  Google Scholar 

  26. Son CN, Bang SY, Cho SK, Sung YK, Kim TH, Bae SC, Jun JB (2014) The frequency of single nucleotide polymorphisms and their association with uric acid concentration based on data from genome-wide association studies in the Korean population. Rheumatol Int 34:777–783

    Article  CAS  PubMed  Google Scholar 

  27. Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Glickman ME, Rao SR, Schultz MR (2014) False discovery rate control is a recommended alternative to Bonferroni-type adjustments in health studies. J Clin Epidemiol 67:850–857

    Article  PubMed  Google Scholar 

  29. Davies NM, von Hinke Kessler Scholder S, Farbmacher H, Burgess S, Windmeijer F, Smith GD (2015) The many weak instruments problem and Mendelian randomization. Stat Med 34:454–468

    Article  PubMed  Google Scholar 

  30. Ja H (1978) Specification tests in econometrics. Econometrica 46:1251–1271

    Article  Google Scholar 

  31. Burgess S, Daniel RM, Butterworth AS, Thompson SG, E-IC (2015) Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol 44:484–495

    Article  PubMed  Google Scholar 

  32. Freeman G, Cowling BJ, Schooling CM (2013) Power and sample size calculations for Mendelian randomization studies using one genetic instrument. Int J Epidemiol 42:1157–1163

    Article  PubMed  Google Scholar 

  33. Dalbeth N, Topless R, Flynn T, Cadzow M, Bolland MJ, Merriman TR (2015) Mendelian randomisation analysis to examine for a causal effect of urate on bone mineral density. J Bone Miner Res 30:985–991

    Article  CAS  PubMed  Google Scholar 

  34. 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 16:336–340

    Article  PubMed  Google Scholar 

  35. Bonora E, Targher G, Zenere MB et al (1996) Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study. Int J Obes Relat Metab Disord 20:975–980

    CAS  PubMed  Google Scholar 

  36. McAdams DeMarco MA, Maynard JW, Baer AN, Gelber AC, Young JH, Alonso A, Coresh J (2012) Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the atherosclerosis risk in communities cohort study. Arthritis Rheum 64:121–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sumino H, Ichikawa S, Kanda T, Nakamura T, Sakamaki T (1999) Reduction of serum uric acid by hormone replacement therapy in postmenopausal women with hyperuricaemia. Lancet 354:650

    Article  CAS  PubMed  Google Scholar 

  38. Hui JY, Choi JW, Mount DB, Zhu Y, Zhang Y, Choi HK (2012) The independent association between parathyroid hormone levels and hyperuricemia: a national population study. Arthritis Res Ther 14:R56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Takahashi S, Yamamoto T, Moriwaki Y, Tsutsumi Z, Yamakita J, Higashino K (1998) Decreased serum concentrations of 1,25(OH)2-vitamin D3 in patients with gout. Metabolism 47:336–338

    Article  CAS  PubMed  Google Scholar 

  40. Chen W, Roncal-Jimenez C, Lanaspa M, Gerard S, Chonchol M, Johnson RJ, Jalal D (2014) Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo. Metabolism 63:150–160

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all participants for their cooperation as well as Yi Wang, PhD (Fudan University, Shanghai China) for statistical support. This study was supported by the National Basic Research Program of China (2014CB942903), the National Natural Science Foundation of China (81170803 and 81370978), the Frontier Technology Joint Research Program of the Shanghai Municipal Hospitals (SHDC 12013115), the Shanghai Leading Talents Award (051), the Science and Technology Commission of Chongqing Municipality (CSTC2013jcyjC00009), the Science and Technology Commission of Shanghai Municipality (14JC1405000), and the Ningbo Science and Technology Plan Projects (2015C50031).

Author information

Authors and Affiliations

  1. Geriatric Department of Ningbo First Hospital, 59 Liu-Ting St, Ningbo, 315010, China

    A. Xiong, Q. Yao & J. Yu

  2. Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yi-Shan Rd, Shanghai, 200233, China

    J. He, W. Fu & Z. Zhang

Authors
  1. A. Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Q. Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to J. Yu or Z. Zhang.

Ethics declarations

Conflicts of interest

None.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Table 1

Analysis of association of weighted UA transporter genetic score with tested confounders by linear regression (DOC 31 kb)

Supplemental Table 2

Mendelian randomization analysis conducted in female groups on BMD and SUA levels (DOC 35 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiong, A., Yao, Q., He, J. et al. No causal effect of serum urate on bone-related outcomes among a population of postmenopausal women and elderly men of Chinese Han ethnicity—a Mendelian randomization study. Osteoporos Int 27, 1031–1039 (2016). https://doi.org/10.1007/s00198-015-3341-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-015-3341-5

Keywords

Search

Navigation