FRI0532 THE IMPACT OF GENETICALLY DETERMINED SERUM URATE LEVELS ON THE DEVELOPMENT OF CARDIOVASCULAR DISEASES: A SYSTEMATIC REVIEW AND META-ANALYSIS OF MENDELIAN RANDOMIZATION STUDIES
Authors: J. Choi, N. Mccormick, S. Marozoff, M. De Vera, H. Choi
Journal: Annals of the Rheumatic Diseases (2020)

Background: Conventional observational studies have identified serum urate (SU) as an independent risk factor for cardiovascular diseases (CVDs), 1,2 but the causal relationships remain unsettled, with potential confounding and reverse causality. When applied correctly, Mendelian randomization (MR) employing genetic variants as instrumental variables can eliminate these biases and allow for causal inference. Objectives: To conduct a systematic review and meta-analysis of English-language, peer-reviewed MR studies on the causal effects of SU on CVDs and assess validation of key MR assumptions. Methods: A research librarian conducted a search (inception to January 2020) of four databases (Medline, Embase, Cochrane Library, and Web of Science), which was supplemented by hand-search. Titles and abstracts were screened by two independent reviewers, who subsequently evaluated and extracted data from full-text of selected articles. Pooled meta-analysis was performed using random-effects weighting. Results: Of 1014 articles identified, 40 were selected for full-text review and 13 studies reporting on CVDs were included in the systematic review (Figure 1). The first was published in 2009 and five were published in 2018 or 2019 alone. The included studies were of varying quality in regards to satisfying the assumptions for MR design. Fig. 1 : PRISMA flow diagram. Overall, there was little evidence for a causal association between SU and risk of CVDs (Table 1). Random-effects meta-analysis revealed that SU was not significantly associated with risk of CVDs (OR=1.04; 95% CI=0.99-1.09) (Figure 2). 11 of the 13 studies reported null estimates for the effects of genetically-determined SU levels on CVDs. Two studies with small numbers of cases (N=125 and 222) reported significant associations, but these pertained to highly-specific subgroups. Table 1. Summary of included studies. CAD: Coronary Artery Disease; CHD: Coronary Heart Disease; IHD: Ischaemic heart disease; MI: Myocardial Infarction; MR: Mendelian Randomization; PVD: Peripheral Vascular Disease; SNP: Single Nucleotide Polymorphism First author; year Number of SNPs analyzed Outcome (n cases) Power MR criteria validated: 1. relevance 2. pleiotropy 3. confounding Conclusion Stark; 2009 10 separately CAD (1,473) 30%-66% 1, 3 Null Yang; 2010 8 combined CHD (3,050) &lt;80% 1, 2, 3 Null Palmer; 2013 1 (rs7442295) IHD (3,742) N/A 1, 2*, 3 Null Kleber; 2015 8 combined CAD (2,418) PVD (295) N/A 1, 2, 3 Null Han; 2015 2 separately CHD (1,146) 80% 1, 2*, 3 Null Testa; 2015 1 (rs734553) CVD events (CVD death, stroke, MI) (222) N/A 1, 2* Significant for CV events White; 2016 31 combined CAD (65,877) 83% 1, 2, 3 Null Keenan; 2016 14 combined CHD (54,501) Stroke (14,779) &gt;80% 1, 2, 3 Null Li; 2018 31 combined IHD (9,467) MI (3,625) 70% 1, 2, 3 Null Li; 2019 31 combined CHD (60,801) MI (43,676) Stroke (10,307) N/A 1, 2, 3 Null Macias-Kauffer; 2019 2 separately CAD (704) N/A 1, 2*, 3 Null Efstathiadou; 2019 28 separately CHD (184,305) MI (54,162) Stroke (514,791) &gt;80% 1, 2, 3 Null Chiang; 2019 8 combined CHD (125) Stroke (57) N/A 1, 2, 3 Significant for CHD * Risk of pleiotropy (assumption 2) is low when utilizing few well-established SNPs Fig. 2 : Pooled meta-analysis results. Conclusion: Evidence from this systematic review does not support a causal role for SU levels and CVDs. As such, interventions targeting SU levels alone are unlikely to lower the risk of CVDs. References: [1] Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007-2008. Am J Med 2012;125:679-87 e1. [2] Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 2007;116:894-900 Disclosure of Interests: Jeewoong Choi: None declared, Natalie McCormick: None declared, Shelby Marozoff: None declared, Mary De Vera: None declared, Hyon Choi Grant/research support from: Ironwood, Horizon, Consultant of: Takeda, Selecta, Horizon, Kowa, Vaxart, Ironwood