Plasma urate and risk of Parkinson's disease: A mendelian randomization study
Camilla J. Kobylecki MD, PhD
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Search for more papers by this authorBørge G. Nordestgaard MD, DMSc
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark
Search for more papers by this authorCorresponding Author
Shoaib Afzal MD, PhD
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Address correspondence to Dr Shoaib Afzal, Chief Physician, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail: [email protected]Search for more papers by this authorCamilla J. Kobylecki MD, PhD
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Search for more papers by this authorBørge G. Nordestgaard MD, DMSc
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark
Search for more papers by this authorCorresponding Author
Shoaib Afzal MD, PhD
Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
Address correspondence to Dr Shoaib Afzal, Chief Physician, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail: [email protected]Search for more papers by this authorAbstract
Objective
Urate is a potent antioxidant, and high plasma urate has been associated with lower incidence of Parkinson's disease (PD) in epidemiological studies. We tested the hypothesis that high concentrations of plasma urate are associated with low incidence of PD.
Methods
We performed observational and genetic analyses using plasma urate and the urate SLC2A9 rs7442295 and ABCG2 rs2231142 genotype in >102,000 individuals from the CGPS (Copenhagen General Population Study). Information on PD and mortality was from national patient and death registries. Incidences of PD were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses.
Results
In total, 398 individuals were diagnosed with PD, of which 285 were incident cases. The multivariable adjusted hazard ratio for PD was 0.56 (95% confidence interval [CI], 0.41–0.77) for the highest versus the lowest tertile of plasma urate (p for trend across 3 groups, 8 × 10–5). Each one-allele increase in the combined allele score was associated with 19μmol/l (95% CI, 18.5–19.9) higher plasma urate. In observational analyses, a 50μmol/l higher plasma urate was associated with a hazard ratio of 0.85 (0.77–0.92) for PD; in instrumental variable analyses, 50μmol/l higher plasma urate was associated with an odds ratio of 1.20 (0.85–1.71) for PD.
Interpretation
High plasma urate was associated with lower risk of PD in observational analyses; however, in instrumental variable analysis, high plasma urate was not associated with low risk of PD. Thus, our data do not support a causal relationship between high plasma urate and low risk of PD. Ann Neurol 2018;84:178–190
Potential Conflicts of Interest
Nothing to report.
Supporting Information
| Filename | Description |
|---|---|
| ana25292-supp-0001-Supinfo01.docxWord 2007 document , 19 KB | Supporting Information Table 1 |
| ana25292-supp-0002-Supinfo02.tiffTIFF image, 650 KB | Supporting Information Table 2 |
| ana25292-supp-0003-Supinfo03.tiffTIFF image, 1.1 MB | Supporting Information Table 3 |
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References
- 1Elbaz A, Bower JH, Maraganore DM, et al. Risk tables for parkinsonism and Parkinson's disease. J Clin Epidemiol 2002; 55: 25–31.
- 2Shults CW. Lewy bodies. Proc Natl Acad Sci U S A 2006; 103: 1661–1668.
- 3Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 2013; 62: 132–144.
- 4Becker BF. Towards the physiological function of uric acid. Free Radic Biol Med 1993; 14: 615–631.
- 5Davis JW, Grandinetti A, Waslien CI, et al. Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease. Am J Epidemiol 1996; 144: 480–484.
- 6de Lau LM, Koudstaal PJ, Hofman A, et al. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005; 58: 797–800.
- 7Weisskopf MG, O'Reilly E, Chen H, et al. Plasma urate and risk of Parkinson's disease. Am J Epidemiol 2007; 166: 561–567.
- 8De Vera M, Rahman MM, Rankin J, et al. Gout and the risk of Parkinson's disease: a cohort study. Arthritis Rheum 2008; 59: 1549–1554.
- 9Schwarzschild MA, Schwid SR, Marek K, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol 2008; 65: 716–723.
- 10Ascherio A, LeWitt PA, Xu K, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol 2009; 66: 1460–1468.
- 11Jain S, Ton TG, Boudreau RM, et al. The risk of Parkinson disease associated with urate in a community-based cohort of older adults. Neuroepidemiology 2011; 36: 223–229.
- 12Moccia M, Picillo M, Erro R, et al. Presence and progression of non-motor symptoms in relation to uric acid in de novo Parkinson's disease. Eur J Neurol 2015; 22: 93–98.
- 13Gao X, O'Reilly EJ, Schwarzschild MA, et al. Prospective study of plasma urate and risk of Parkinson disease in men and women. Neurology 2016; 86: 520–526.
- 14Church WH, Ward VL. Uric acid is reduced in the substantia nigra in Parkinson's disease: effect on dopamine oxidation. Brain Res Bull 1994; 33: 419–425.
- 15Chen X, Burdett TC, Desjardins CA, et al. Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration. Proc Natl Acad Sci U S A 2013; 110: 300–305.
- 16Gong L, Zhang QL, Zhang N, et al. Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: linking to Akt/GSK3beta signaling pathway. J Neurochem 2012; 123: 876–885.
- 17Guerreiro S, Ponceau A, Toulorge D, et al. Protection of midbrain dopaminergic neurons by the end-product of purine metabolism uric acid: potentiation by low-level depolarization. J Neurochem 2009; 109: 1118–1128.
- 18Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008; 27: 1133–1163.
- 19Smith GD. Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health. Genes Nutr 2011; 6: 27–43.
- 20Noyce AJ, Nalls MA. Mendelian randomization—the key to understanding aspects of Parkinson's disease causation? Mov Disord 2016; 31: 478–483.
- 21Smith GD, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol 2003; 32: 1–22.
- 22Wallace C, Newhouse SJ, Braund P, et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet 2008; 82: 139–149.
- 23Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40: 437–442.
- 24Woodward OM, Kottgen A, Coresh J, et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci U S A 2009; 106: 10338–10342.
- 25Wermuth L, Lassen CF, Himmerslev L, et al. Validation of hospital register-based diagnosis of Parkinson's disease. Dan Med J 2012; 59: A4391.
- 26Kottgen A, Albrecht E, Teumer A, et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 2013; 45: 145–154.
- 27Keenan T, Zhao W, Rasheed A, et al. Causal assessment of serum urate levels in cardiometabolic diseases through a mendelian randomization study. J Am Coll Cardiol 2016; 67: 407–416.
- 28White J, Sofat R, Hemani G, et al. Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol 2016; 4: 327–336.
- 29Thomsen M, Nordestgaard BG. Myocardial infarction and ischemic heart disease in overweight and obesity with and without metabolic syndrome. JAMA Intern Med 2014; 174: 15–22.
- 30Brondum-Jacobsen P, Nordestgaard BG, Schnohr P, et al. 25-hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis. Ann Neurol 2013; 73: 38–47.
- 31Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, et al. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol 2015; 77: 301–311.
- 32Afzal S, Bojesen SE, Nordestgaard BG. Low 25-hydroxyvitamin D and risk of type 2 diabetes: a prospective cohort study and metaanalysis. Clin Chem 2013; 59: 381–391.
- 33Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604–612.
- 34Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.
- 35Palmer TM, Sterne JA, Harbord RM, et al. Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses. Am J Epidemiol 2011; 173: 1392–1403.
- 36Tchetgen EJ, Walter S, Vansteelandt S, et al. Instrumental variable estimation in a survival context. Epidemiology 2015; 26: 402–410.
- 37Lill CM, Roehr JT, McQueen MB, et al. Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: the PDGene database. PLoS Genet 2012; 8: e1002548.
- 38Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 2014; 46: 989–993.
- 39Collins R. What makes UK Biobank special? Lancet 2012; 379: 1173–1174.
- 40Sudlow C, Gallacher J, Allen N, et al. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLoS Med 2015; 12: e1001779.
- 41Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 2013; 37: 658–665.
- 42Harbord RM, Didelez V, Palmer TM, et al. Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies. Stat Med 2013; 32: 1246–1258.
- 43O'Reilly EJ, Gao X, Weisskopf MG, et al. Plasma urate and Parkinson's disease in women. Am J Epidemiol 2010; 172: 666–670.
- 44Pellecchia MT, Savastano R, Moccia M, et al. Lower serum uric acid is associated with mild cognitive impairment in early Parkinson's disease: a 4-year follow-up study. J Neural Transm (Vienna) 2016; 123: 1399–1402.
- 45Alonso A, Rodriguez LA, Logroscino G, et al. Gout and risk of Parkinson disease: a prospective study. Neurology 2007; 69: 1696–1700.
- 46Schernhammer E, Qiu J, Wermuth L, et al. Gout and the risk of Parkinson's disease in Denmark. Eur J Epidemiol 2013; 28: 359–360.
- 47Pakpoor J, Seminog OO, Ramagopalan SV, et al. Clinical associations between gout and multiple sclerosis, Parkinson's disease and motor neuron disease: record-linkage studies. BMC Neurol 2015; 15: 16.
- 48Gao J, Xu H, Huang X, et al. Short communication: genetic variations of SLC2A9 in relation to Parkinson's disease. Transl Neurodegener 2013; 2: 5.
- 49Gonzalez-Aramburu I, Sanchez-Juan P, Jesus S, et al. Genetic variability related to serum uric acid concentration and risk of Parkinson's disease. Mov Disord 2013; 28: 1737–1740.
- 50Facheris MF, Hicks AA, Minelli C, et al. Variation in the uric acid transporter gene SLC2A9 and its association with AAO of Parkinson's disease. J Mol Neurosci 2011; 43: 246–250.
- 51Simon KC, Eberly S, Gao X, et al. Mendelian randomization of serum urate and Parkinson disease progression. Ann Neurol 2014; 76: 862–868.
- 52Burgess S. Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome. Int J Epidemiol 2014; 43: 922–929.
- 53Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol 2011; 40: 755–764.
- 54Smith GD, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 2014; 23: R89–R98.
- 55Taylor AE, Davies NM, Ware JJ, et al. Mendelian randomization in health research: using appropriate genetic variants and avoiding biased estimates. Econ Hum Biol 2014; 13: 99–106.
- 56Schwarzschild MA, Ascherio A, Beal MF, et al. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol 2014; 71: 141–150.
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