Top

Osteoporosis International

Published in:

01-03-2016 | Original Article

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

Authors: A. Xiong, Q. Yao, J. He, W. Fu, J. Yu, Z. Zhang

Published in: Osteoporosis International | Issue 3/2016

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.

Available only for authorised users

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 314:197–207CrossRefPubMed

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 301:119–127CrossRefPubMed

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 47:668–673CrossRefPubMed

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 78:6858–6862CrossRef

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 107:14351–14356CrossRefPubMedPubMedCentral

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 26:955–964CrossRefPubMed

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 24:2961–2970CrossRefPubMed

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 52:400–406CrossRefPubMed

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 25:1099–1105CrossRefPubMed

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 29:1701–1707CrossRefPubMedPubMedCentral

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 58:46–52CrossRefPubMedPubMedCentral

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 25:1837–1844CrossRefPubMed

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 30:992–999CrossRefPubMedPubMedCentral

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 64:438–446CrossRefPubMed

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 21:223–242CrossRefPubMedPubMedCentral

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 45:145–154CrossRefPubMed

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 43:1127–1130CrossRefPubMed

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 7:10CrossRefPubMedPubMedCentral

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 54:2561–2569CrossRefPubMed

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 85:344–351CrossRefPubMed

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 7:830–837CrossRefPubMedPubMedCentral

22.

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

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:e47264CrossRefPubMedPubMedCentral

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 31:977–983CrossRefPubMedPubMedCentral

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, e1000504CrossRefPubMedPubMedCentral

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 34:777–783CrossRefPubMed

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 81:559–575CrossRefPubMedPubMedCentral

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 67:850–857CrossRefPubMed

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 34:454–468CrossRefPubMed

30.

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

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 44:484–495CrossRefPubMed

32.

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

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 30:985–991CrossRefPubMed

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 16:336–340CrossRefPubMed

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 20:975–980PubMed

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 64:121–129CrossRefPubMedPubMedCentral

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 354:650CrossRefPubMed

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:R56CrossRefPubMedPubMedCentral

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 47:336–338CrossRefPubMed

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 63:150–160CrossRefPubMed

Title: 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
Authors: A. Xiong
Q. Yao
J. He
W. Fu
J. Yu
Z. Zhang
Publication date: 01-03-2016
Publisher: Springer London
Published in: Osteoporosis International / Issue 3/2016
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-015-3341-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2016

The effects of visceral obesity and androgens on bone: trenbolone protects against loss of femoral bone mineral density and structural strength in viscerally obese and testosterone-deficient male rats

Correlations among four measures of thoracic kyphosis in older adults

The effects of state-level expenditures for home- and community-based services on the risk of becoming a long-stay nursing home resident after hip fracture

Risk factors for hip fracture in very old people: a population-based study

Patients with prior vertebral or hip fractures treated with teriparatide in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study

Effect of osteoporosis medications on fracture healing