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Palmer, Tom M.; Nordestgaard, Børge G.; Benn, Marianne; Tybjærg-Hansen, Anne; Smith, George Davey; Lawlor, Debbie A.; Timpson, Nicholas J. (2013)
Publisher: BMJ Publishing Group Ltd.
Languages: English
Types: Article
Subjects: R1, RA

Classified by OpenAIRE into

mesheuropmc: nutritional and metabolic diseases, urologic and male genital diseases
Objectives: To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index.\ud Design: Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index).\ud Setting: Two large, prospective cohort studies in Denmark.\ud Participants: We measured levels of uric acid and related covariables in 58 072 participants from the Copenhagen General Population Study and 10 602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively.\ud Main outcome: Blood pressure and prospectively assessed ischaemic heart disease.\ud Results: Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%).\ud Conclusion: By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1 Ames BN, Cathcart R, Schwiers E, Hochstein P. 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 1981;78:6858-62.
    • 2 Phay JE, Hussain HB, Moley JF. Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). Genomics 2000;66:217-20.
    • 3 Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CNA, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008;40:437-42.
    • 4 Wu X, Muzny DM, Chi Lee C, Thomas Caskey C. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992;34:78-84.
    • 5 Nesse RM, Williams GC. Evolution and healing: the new science of Darwinian medicine. Phoenix, 1996.
    • 6 Liese AD, Hense HW, Lowel H, Doring A, Tietze M, Keil U. Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. Epidemiology 1999;10:391-7.
    • 7 Alderman M, Aiyer KJV. Uric acid: role in cardiovascular disease and effects of losartan. Curr Med Res Opin 2004;20:369-79.
    • 8 Sundstrom J, Sullivan L, D'Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 2005;45:28-33.
    • 9 Perlstein TS, Gumieniak O, Williams GH, Sparrow D, Vokonas PS, Gaziano M, et al. Uric acid and the development of hypertension. Hypertension 2006;48:1031-6.
    • 10 Bos MJ, Koudstaal PJ, Hofman A, Witteman JCM, Breteler MMB. Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 2006;37:1503-7.
    • 11 Deveci OS, Kabakci G, Okutucu S, Tulumen E, Aksoy H, Kaya EB, et al. The association between serum uric acid level and coronary artery disease. Int J Clin Pract 2010;64:900-7.
    • 12 Fang J, Alderman MH. Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic follow-up study, 1971-1992. JAMA 2000;283:2404-10.
    • 13 Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Care Res 2009;61:885-92.
    • 14 Meisinger C, Koenig W, Baumert J, Doring A. Uric acid levels are associated with all-cause and cardiovascular disease mortality independent of systemic inflammation in men from the general population: the MONICA/KORA cohort study. Arterioscler Thromb Vasc Biol 2008;28:1186-92.
    • 15 Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res 2010;62:170-80.
    • 16 Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003;41:1183-90.
    • 17 Davey Smith G, Ebrahim S. 'Mendelian Randomisation': can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003;32:1-22.
    • 18 Burgess S, Butterworth A, Malarstig A, Thompson SG. Use of Mendelian randomisation to assess potential benefit of clinical intervention. BMJ 2012;345:e7325.
    • 19 Wallace C, Newhouse SJ, Braund P, Zhang F, Tobin M, Falchi M, et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet 2008;82:139-49.
    • Wright AF, Rudan I, Hastie ND, Campbell H. A 'complexity' of urate transporters. Kidney Int 2010;78:446-52.
    • Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308.
    • Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50:2173-95.
    • Sethi AA, Nordestgaard BG, Agerholm-Larsen B, Frandsen E, Jensen G, Tybjaerg-Hansen A. Angiotensinogen polymorphisms and elevated blood pressure in the general population: the Copenhagen City Heart Study. Hypertension 2001;37:875-81.
    • Tobin MD, Sheehan NA, Scurrah KJ, Burton PR. Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure. Stat Med 2005;24:2911-35.
    • Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450-61.
    • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010;42:937-48.
    • Thomas DC, Lawlor DA, Thompson JR. Re: Estimation of bias in nongenetic observational studies using “Mendelian triangulation” by Bautista et al. Ann Epidemiol 2007;17:511-3.
    • Angrist JD, Imbens GW. Two-stage least squares estimation of average causal effects in models with variable treatment intensity. J Am Stat Soc 1995;90:431-42.
    • Harris R. metan: fixed- and random-effects meta-analysis. Stata J 2008;8:3-28.
    • Timpson NJ, Nordestgaard BG, Harbord RM, Zacho J, Frayling TM, Tybjarg-Hansen A, et al. C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int J Obes 2011;35:300-8.
    • Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 2009;373:1083-96.
    • Zheng W, McLerran DF, Rolland B, Zhang X, Inoue M, Matsuo K, et al. Association between body-mass index and risk of death in more than 1 million Asians. N Engl J Med 2011;364:719-29.
    • Timpson NJ, Harbord R, Davey Smith G, Zacho J, Tybjaerg-Hansen A, Nordestgaard BG. Does greater adiposity increase blood pressure and Hypertension risk? Mendelian randomization using the FTO/MC4R genotype. Hypertension 2009;54:84-90.
    • Nordestgaard BG, Palmer TM, Benn M, Zacho J, Tybjaerg-Hansen A, Davey Smith G, et al. The effect of elevated body mass index on ischemic heart disease risk: causal estimates from a Mendelian randomisation approach. PLoS Med 2012;9:e1001212.
    • 35 36 37 38 39 40 41 42 43 44 45 Brandstatter A, Kiechl S, Kollerits B, Hunt SC, Heid IM, Coassin S, et al. Sex-specific association of the putative fructose transporter slc2a9 variants with uric acid levels is modified by BMI. Diabetes Care 2008;31:1662-7.
    • Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach. PLoS One 2012;7:e39321.
    • Ishizaka N, Ishizaka Y, Toda A, Tani M, Koike K, Yamakado M, et al. Changes in waist circumference and body mass index in relation to changes in serum uric acid in Japanese individuals. J Rheumatol 2010;37:410-6.
    • Stark K, Reinhard W, Grassl M, Erdmann J, Schunkert H, Illig T, et al. Common polymorphisms influencing serum uric acid levels contribute to susceptibility to gout, but not to coronary artery disease. PLoS One 2009;4:e7729.
    • Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study. Ann Intern Med 1999;131:7-13.
    • Strasak A, Ruttmann E, Brant L, Kelleher C, Klenk J, Concin H, et al. Serum uric acid and risk of cardiovascular mortality: a prospective long-term study of 83 683 Austrian men. Clin Chem 2008;54:273-84.
    • McKeigue PM, Campbell H, Wild S, Vitart V, Hayward C, Rudan I, et al. Bayesian methods for instrumental variable analysis with genetic instruments (“Mendelian randomization”): example with urate transporter SLC2A9 as instrumental variable for effect of urate levels on metabolic syndrome. Int J Epidemiol 2010;39:907-18.
    • Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, Doblado M, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 2008;5:e197.
    • Yang Q, Kottgen A, Dehghan A, Smith AV, Glazer NL, Chen MH, et al. Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet 2010;3:523-30.
    • Parsa A, Brown E, Weir MR, Fink JC, Shuldiner AR, Mitchell BD, et al. Genotype-based changes in serum uric acid affect blood pressure. Kidney Int 2012;81:502-7.
    • Int J Epidemiol 2004;33:30-42.
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