Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts

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. 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). Setting Two large, prospective cohort studies in Denmark. 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. Main outcome Blood pressure and prospectively assessed ischaemic heart disease. 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%). 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.

[1]  T. Frayling,et al.  C-reactive protein levels and body mass index: Elucidating direction of causation through reciprocal Mendelian randomization , 2010, International Journal of Obesity.

[2]  J. Angrist,et al.  Two-Stage Least Squares Estimation of Average Causal Effects in Models with Variable Treatment Intensity , 1995 .

[3]  Daniel Levy,et al.  Serum Uric Acid and Risk for Cardiovascular Disease and Death: The Framingham Heart Study , 1999, Annals of Internal Medicine.

[4]  N. Timpson,et al.  The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach , 2012, PLoS medicine.

[5]  D. Hernandez,et al.  Multiple Genetic Loci Influence Serum Urate Levels and Their Relationship With Gout and Cardiovascular Disease Risk Factors , 2010, Circulation. Cardiovascular genetics.

[6]  A. Shuldiner,et al.  Genotype-based changes in serum uric acid affect blood pressure. , 2012, Kidney international.

[7]  N. Timpson,et al.  Does Greater Adiposity Increase Blood Pressure and Hypertension Risk?: Mendelian Randomization Using the FTO/MC4R Genotype , 2009, Hypertension.

[8]  Tanya M. Teslovich,et al.  Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index , 2010 .

[9]  Nuala A Sheehan,et al.  Adjusting for treatment effects in studies of quantitative traits: antihypertensive therapy and systolic blood pressure , 2005, Statistics in medicine.

[10]  D. Levy,et al.  Relations of Serum Uric Acid to Longitudinal Blood Pressure Tracking and Hypertension Incidence , 2005, Hypertension.

[11]  Liu Jing-yan.  Association between Serum Uric Acid Level and Coronary Artery Disease , 2012 .

[12]  H. Schumacher,et al.  Febuxostat compared with allopurinol in patients with hyperuricemia and gout. , 2005, The New England journal of medicine.

[13]  William A. Richardson,et al.  SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout , 2008, Nature Genetics.

[14]  K. Tuttle,et al.  Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? , 2003, Hypertension.

[15]  Juan P Casas,et al.  Estimation of bias in nongenetic observational studies using "mendelian triangulation". , 2006, Annals of epidemiology.

[16]  R. Nesse,et al.  Evolution and Healing: The New Science of Darwinian Medicine , 1994 .

[17]  D. Muzny,et al.  Two independent mutational events in the loss of urate oxidase during hominoid evolution , 2004, Journal of Molecular Evolution.

[18]  J. Erdmann,et al.  Common Polymorphisms Influencing Serum Uric Acid Levels Contribute to Susceptibility to Gout, but Not to Coronary Artery Disease , 2009, PloS one.

[19]  F. Kronenberg,et al.  Sex-Specific Association of the Putative Fructose Transporter SLC2A9 Variants With Uric Acid Levels Is Modified by BMI , 2008, Diabetes Care.

[20]  D. Lawlor,et al.  Re: Estimation of bias in nongenetic observational studies using "Mendelian triangulation" by Bautista et al. , 2007, Annals of epidemiology.

[21]  Hyon K. Choi,et al.  Hyperuricemia and risk of stroke: a systematic review and meta-analysis. , 2009, Arthritis and rheumatism.

[22]  Fred S Apple,et al.  Universal definition of myocardial infarction. , 2007, Journal of the American College of Cardiology.

[23]  Hyon K. Choi,et al.  Hyperuricemia and coronary heart disease: A systematic review and meta‐analysis , 2010, Arthritis care & research.

[24]  M. Alderman,et al.  Uric acid: role in cardiovascular disease and effects of losartan , 2004, Current medical research and opinion.

[25]  A. Hofman,et al.  Uric Acid Is a Risk Factor for Myocardial Infarction and Stroke: The Rotterdam Study , 2006, Stroke.

[26]  C. Meisinger,et al.  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 , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[27]  P. Vokonas,et al.  Uric Acid and the Development of Hypertension: The Normative Aging Study , 2006, Hypertension.

[28]  Chien-Jen Chen,et al.  Association between body-mass index and risk of death in more than 1 million Asians. , 2011, The New England journal of medicine.

[29]  E Budtz-Jørgensen,et al.  Prenatal methylmercury exposure as a cardiovascular risk factor at seven years of age. , 1999, Epidemiology.

[30]  G. Jensen,et al.  Angiotensinogen Polymorphisms and Elevated Blood Pressure in the General Population: The Copenhagen City Heart Study , 2001, Hypertension.

[31]  J. Moley,et al.  Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9). , 2000, Genomics.

[32]  Kuan-Hung Lin,et al.  Uric acid and the development of hypertension. , 2010, Medical science monitor : international medical journal of experimental and clinical research.

[33]  Mario Falchi,et al.  Genome-wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and Dyslipidemia , 2022 .

[34]  P. Elliott,et al.  SLC2A9 Is a High-Capacity Urate Transporter in Humans , 2008, PLoS medicine.

[35]  S. Wild,et al.  Bayesian methods for instrumental variable analysis with genetic instruments (‘Mendelian randomization’): example with urate transporter SLC2A9 as an instrumental variable for effect of urate levels on metabolic syndrome , 2010, International journal of epidemiology.

[36]  Douglas G. Altman,et al.  Metan: Fixed- and Random-Effects Meta-Analysis , 2008 .

[37]  S. Ebrahim,et al.  'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? , 2003, International journal of epidemiology.

[38]  Jing Fang,et al.  Serum Uric Acid and Cardiovascular Mortality: The NHANES I Epidemiologic Follow-up Study, 1971-1992 , 2000 .

[39]  B. Ames,et al.  Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Klenk,et al.  Serum uric acid and risk of cardiovascular mortality: a prospective long-term study of 83,683 Austrian men. , 2008, Clinical chemistry.

[41]  R. Collins,et al.  Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies , 2009, The Lancet.

[42]  V. Rousson,et al.  Serum Uric Acid and Adiposity: Deciphering Causality Using a Bidirectional Mendelian Randomization Approach , 2012, PloS one.

[43]  A. Butterworth,et al.  Use of Mendelian randomisation to assess potential benefit of clinical intervention , 2012, BMJ : British Medical Journal.

[44]  N. Hastie,et al.  A 'complexity' of urate transporters. , 2010, Kidney international.

[45]  K. Koike,et al.  Changes in Waist Circumference and Body Mass Index in Relation to Changes in Serum Uric Acid in Japanese Individuals , 2010, The Journal of Rheumatology.

[46]  B. Nordestgaard,et al.  Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. , 2007, JAMA.

[47]  S. Ebrahim,et al.  Mendelian randomization: prospects, potentials, and limitations. , 2004, International journal of epidemiology.