Supplementary table S2 General characteristics and main findings of the systematic reviews of observational studies Author Year Population Study design Comparison Outcome N studies Authors' interpretation Cardiovascular Outcomes Baker1 2005 Healthy subjects Cohort SUA level CVD 10 The excess risk associated with SUA in healthy patients is likely to be small. High SUA is likely an independent risk factor in patients at high CVD risk. Baker1 2005 Patients at high CVD risk Cohort SUA level CVD 11 Strazzullo2 2007 General Cohort SUA level CVD 16 SUA is a very weak predictor of CVD in healthy population, but a significant independent predictor among subjects at high or very high risk. Strazzullo2 2007 Patients with arterial hypertension Cohort SUA level CVD 8 Strazzullo2 2007 Patients at high CVD risk Cohort SUA level CVD 5 Barron ADDIN EN.CITE 2015 General Cohort SUA level CVD 3 Greater risk of CVD/all-cause mortality in those with the highest than with the lowest quartiles of SUA. Dimitroula4 2008 General Cohort SUA level Stroke 13 It remains controversial whether elevated serum uric acid is neuroprotective or injurious at the onset of acute stroke. Hwu5 2010 General SUA level Hypertension 6 All except one study have documented a direct association with either incident hypertension or increase in blood pressure. Hwu5 2010 General Hyper vs normal Hypertension 17 Kidney disease control
Jiang24 2016 Prehypertension General Highest vs lowest SUA category 8 44,095 20,832 OR Random 1.84 (1.42, 2.38) Zhang13 2016 Left atrial thrombus or spontaneous echo contrast (LATH/LASEC) Patients with mitral stenosis, sinus rhythm or atrial fibrillation Highest vs lowest SUA category 6 2,381 241 OR Random 1.59 (1.13, 2.23) Yan ADDIN EN.CITE 2014 Major adverse cardiovascular events (MACE) Acute myocardial infarction (AMI) patients vs controls Hyper vs normal 6 2,406 651 RR Fixed 3.44 (2.33, 5.08) Song ADDIN EN.CITE 2015 MACE Patients after PCI Hyper vs normal 2 3,054 NA RR Fixed 1.78 (1.26, 2.52)
Diabetes related outcomes Jia ADDIN EN.CITE 2013 Impaired fasting glucose or T2DM General Highest vs lowest SUA category 12 62,834 6,340 RR Random 1.57 (1.39, 1.77) Kodama31 2009 Type 2 diabetes (T2DM) General 1 mg/dl SUA increase 11 42,834 3,305 RR Random 1.17 (1.09, 1.25) YES ADDIN EN.CITE Jia ADDIN EN.CITE 2013 T2DM General Highest vs lowest SUA category 9 48,808 5,115 RR Fixed 1.67 (1.51, 1.86) Lv ADDIN EN.CITE 2013 T2DM incidence General without diabetes Hyper vs normal 8 32,016 2,930 RR Fixed 1.56 (1.39, 1.76)
Lv ADDIN EN.CITE 2013 T2DM incidence General without diabetes 1 mg/dl SUA increase 6 21,592 2,203 RR Fixed 1.06 (1.04, 1.07) Qin19 2016 Diabetes incidence Hypertensive patients Hyper vs normal 2 8,247 564 aHR Random 1.84 (1.02, 3.30) Qin19 2016 Diabetes incidence Hypertensive patients Continuous SUA level 2 NA NA aHR Random 1.28 (1.18, 1.38) Xu33 2013 Diabetic nephropathy T2DM patients Continuous/categorical SUA level 3 3,166 196 OR Random 1.91 (1.07, 3.42) Xu33 2013 Diabetic retinopathy T2DM patients Continuous/categorical SUA level 2 1,739 311 OR Random 1.23 (0.81, 1.87) Xu33 2013 Diabetic vascular complications T2DM patients Continuous/categorical SUA level 6 5,017 967 OR Random 1.28 (1.12, 1.46) Xu33 2013 Diabetic microvascular complications T2DM patients Continuous/categorical SUA level 5 4,513 854 OR Random 1.47 (1.11, 1.94) Xu33 2013 Peripheral vascular disease T2DM patients Continuous/categorical SUA level 3 2,538 151 OR Random 1.27 (0.91, 1.78) Xu33 2013 Diabetic Macrovascular disease T2DM patients Continuous/categorical SUA level 3 2,538 187 OR Fixed 1.03 (1.00, 1.06) Xu33 2013 Diabetic neuropathy T2DM patients Continuous/categorical SUA level 2 2,034 231 OR Random 1.19 (0.61, 2.32) NO ADDIN EN.CITE Yu ADDIN EN.CITE 2016 Diabetic peripheral neuropathy Diabetic peripheral peuropathy patients vs diabetic controls SUA level (μmol/L) 7 2,035 464 MD Random 50.03 (22.14, 77.93)
(discordance in statistical significance) Schrag ADDIN EN.CITE 2013 Alzheimer’s disease (AD) AD patients vs controls SUA level ( mg/dl) 10 900 453 Hedge's G Random -0.59 (-1.26, Chen41 2014 Alzheimer’s disease (AD) AD patients vs controls SUA level ( mg/dl) 11 2,708 647 SMD Random -0.50 (-1.23, 0.22) Du42 2016 Alzheimer’s disease (AD) AD patients vs controls SUA level (mg/dl) 21 3,617 1,128 MD Random -0.77 (-1.18, Du42 2016 Alzheimer’s disease (AD) Alzheimer’s patients vs controls Highest vs lowest SUA category 3 7,372 NA RR Fixed 0.66 (0.52, 0.85) Bartoli43 2016 Bipolar disorder Bipolar disorder vs controls SUA level (mg/dl) 9 1,127 619 SMD Random 0.65 (0.33, 0.97) Bartoli43 2016 Bipolar disorder Bipolar disorder vs major depression SUA level (mg/dl) 5 735 399 SMD Random 0.46 (0.16, 0.75) Bartoli43 2016 Bipolar disorder phase (Depressive vs euthymic phase) Depressive vs euthymic phase SUA level (mg/dl) 6 375 NA SMD Random -0.11 (-0.33, 0.11) Bartoli43 2016 Bipolar disorder phase Manic/mixed vs depressive phase SUA level (mg/dl) 7 472 NA SMD Random 0.34 (0.02, 0.66) Bartoli43 2016 Bipolar disorder phase Manic/mixed vs euthymic phase SUA level (mg/dl) 6 402 NA SMD Random 0.19 (-0.10, 0.49) Khan39 2013 Dementia/cognitive impairment Dementia/cognitive impairment patients vs controls SUA level (mg/dl) 31 7,021 2,681 SMD Random -0.33 (-0.48,
Khan39 2013 Dementia/cognitive impairment Dementia/cognitive impairment patients vs controls Highest vs lowest SUA category 5 3,281 489 OR Random 1.18 (0.96, 1.46) Khan39 2013 Vascular dementia (VaD) Vascular dementia patients vs controls SUA level ( mg/dl) 7 597 272 SMD Random -0.05 (-0.88, 0.78) Schrag ADDIN EN.CITE 2013 Mild cognitive impairment (MCI) MCI patients vs controls SUA level ( mg/dl) 2 129 49 Hedge's G Random -0.73 (-2.7, 1.24) YES ADDIN EN.CITE 40 Khan39 2013 Mild cognitive impairment (MCI) MCI patients vs controls SUA level ( mg/dl) 4 731 515 SMD Random -0.24 (-0.90, 0.42) Khan39 2013 Mixed or undifferentiated dementia Mixed or undifferentiated dementia vs controls SUA level ( mg/dl) 4 1,998 NA SMD Random 0.19 (-0.17, 0.54) Khan39 2013 Parkinson’s disease (PD) PD patients vs controls SUA level ( mg/dl) 7 1,008 514 SMD Random -0.67 (-1.05, YES ADDIN EN.CITE 44 44 45 Shen44 2013 Parkinson’s disease (PD) PD patients vs controls SUA level (μM/L) 6 2,493 1,217 SMD NA -0.52 (-0.72, Shen44 2013 Parkinson’s disease (PD) General Hyper vs normal 6 33,185 578 RR Random 0.65 (0.43, 0.97) Shen44 2013 Parkinson’s disease (PD) General Hyper vs normal 3 11,795 NA NA 0.77 (0.68, 0.88) Shen45 2013 PD progression PD patients Hyper vs normal 2 1,578 NA RR Fixed 0.56 (0.43, 0.72) 0.29)
Liu46 2012 Multiple sclerosis (MS) MS patients vs controls SUA level (umol/L) 8 1,037 556 SMD Random -0.68 (-0.82, YES ADDIN EN.CITE 47 Wang47 2016 Multiple sclerosis (MS) MS patients vs SUA level (μmol/L) 10 2,216 1,308 SMD Random -0.40 (-0.73, Wang47 2016 Neruomyelistsopticis (NMO) NMO patients vs SUA level (μmol/L) 3 1,137 229 SMD Random -0.85 (-1.24, Wang47 2016 MS and NMO MS+NMO patients vs control SUA level (μmol/L) 13 2,445 1,537 SMD Random -0.52 (-0.81, Abraham ADDIN EN.CITE 2014 Amyotrophic lateral sclerosis (ALS) ALS patients vs controls SUA level ( mg/dl) 3 826 311 Hedge's G NA 0.84 (NA, NA) Flatow ADDIN EN.CITE 2013 Schizophrenia (Chronic) Chronic Schizophrenia patients vs controls SUA level (mg/dl) 3 241 103 Hedge's G Random p=0.15 0.46)
Flatow ADDIN EN.CITE 2013 Schizophrenia Psychosis) Schizophrenia patients in Psychosis vs controls SUA level (mg/dl) 2 274 155 Hedge's G Random p<0.01 Cancer outcomes Yan ADDIN EN.CITE 2015 Cancer incidence General Highest vs lowest SUA category 5 456,053 14,355 RR Fixed 1.03 (1.01, 1.05) Yan ADDIN EN.CITE 2015 Cancer in Digestive organs incidence General Highest vs lowest SUA category 3 266,347 2,521 RR Random 1.08 (0.94, 1.25) Yan ADDIN EN.CITE 2015 Cancer in Lymphoid and hematopoietic systems incidence General Highest vs lowest SUA category 2 86,739 397 RR Fixed 1.71 (1.10, 2.68)
Trkulja ADDIN EN.CITE 2012 Short-term mortality AMI patients Highest vs lowest SUA category 8 6,805 396 OR Random 2.95 (2.29, 3.80) Trkulja ADDIN EN.CITE 2012 Medium term mortality AMI patients Highest vs lowest SUA category 5 5,194 565 OR Random 2.28 (1.82, 2.86) Yan ADDIN EN.CITE 2014 In-hospital mortality AMI patients vs controls Hyper vs normal 6 5,686 218 RR Random 2.10 (1.03, 4.26) Xu33 2013 Mortality T2DM patients Hyper vs normal 3 5,534 NA HR Random 1.09 (1.03, 1.16)
Huang ADDIN EN.CITE 2014 Combined death or cardiac events Heart failure patients Hyper vs normal 9 12,699 1,765 HR Random 1.39 (1.18, 1.63) Huang ADDIN EN.CITE 2014 Combined death or cardiac events Heart failure patients 1 mg/dl SUA increase 4 2,514 NA HR Random 1.28 (0.97, 1.70) Song ADDIN EN.CITE 2015 Adverse outcomes (mortality, MAGE, In-stent restenosis) Patients after PCI Hyper vs normal 12 21,030 NA RR Random 1.46 (1.29, 1.65) Wang ADDIN EN.CITE 2016 Occurrence of poor outcomes Acute ischemic stroke patients Highest vs lowest SUA category 9 7,932 NA HR Random 0.77 (0.68, 0.88)
* We corrected the errors and inappropriateness of the original meta-analysis, when conducted the quantitative analysis. Supplementary table S4 General characteristics and main findings of the 31 meta-analyses of RCTs Author Year Population therapy Versus Outcome N studies N participants N Cases Type of metric Effect model Reported summary effect (95%) Concordance in overlapped MA Kidney diseases Fink ADDIN EN.CITE 2013 Nephrolithiasis patients Thiazides Placebo/no treatment Nephrolithiasis recurrence 5 300 151 RR Random 0.52 (0.39, 0.69) Fink ADDIN EN.CITE 2013 Nephrolithiasis patients Citrates Placebo/no treatment Nephrolithiasis recurrence 4 197 90 RR Random 0.25 (0.14, 0.44) Fink ADDIN EN.CITE 2013 Nephrolithiasis patients Allopurinol Placebo/no treatment Nephrolithiasis recurrence 2 152 78 RR Random 0.59 (0.42, 0.84) Wang59 2013 General All active therapy Placebo/no treatment SCr (mg/dL) 9 580 NA SMD Random -1.25 (-1.98, Wang59 2013 General All active therapy Placebo/no treatment eGFR (ml/min/1.73m2) 3 218 NA SMD Fixed 0.41 (0.14, 0.68)
Zhang ADDIN EN.CITE 2014 CKD Patients Allopurinol Placebo/no treatment SCr (μmol/L) 6 354 177 MD Random -62.55 (-98.10, YES ADDIN EN.CITE 61 Bose ADDIN EN.CITE 2014 Patients with CKD or decreased kidney function Allopurinol Placebo/no treatment SCr (mg/dL) 3 130 NA MD Random -0.40 (-0.80, 0.00) Zhang ADDIN EN.CITE 2014 CKD Patients Allopurinol Placebo/no treatment eGFR (ml/min/1.73m2) 2 184 96 MD Fixed 5.65 (1.88, 9.41) NO ADDIN EN.CITE 61 (discordance in statistical significance) Bose ADDIN EN.CITE 2014 Patients with CKD or decreased kidney function Allopurinol Placebo/no treatment eGFR (ml/min/1.73m2) 5 346 NA MD Random 3.10 (-0.90, 7.10) Zhang ADDIN EN.CITE 2014 CKD Patients Allopurinol Placebo/no treatment End-stage renal disease 5 267 132 RR Fixed 0.30 (0.19, NO ADDIN EN.CITE
61 (discordance in direction and statistical significance) Bose ADDIN EN.CITE 2014 Patients with CKD or decreased kidney function Allopurinol Placebo/no treatment End-stage kidney disease 2 164 NA RR Random 1.01 (0.15, 6.98) Zhang ADDIN EN.CITE 2014 CKD Patients Allopurinol Placebo/no treatment Blood urea nitrogen (mmol/L) 3 169 83 MD Fixed -6.15 (-8.17, Zhang ADDIN EN.CITE 2014 CKD Patients Allopurinol Placebo/no treatment 24-h urinary protein (g/day) 3 184 94 MD Fixed 0.13 (0.28, 0.02) Zhang ADDIN EN.CITE 2014 CKD Patients Allopurinol Placebo/no treatment Stable renal function 5 267 132 RR Fixed 1.73 (1.44, 2.09)
Bose ADDIN EN.CITE 2014 Patients with CKD or decreased kidney function Allopurinol Placebo/no treatment Proteinuria (g/day) 5 250 NA MD Random -0.20 (-0.60, 0.10) Endothelial function Higgins62 2010 Population with vascular diseases Xanthine Oxidase Placebo/no treatment Flow-mediated dilatation (%) 5 144 75 MD Random 2.50 (0.15, 4.84) Higgins62 2010 Population with vascular diseases Xanthine Oxidase Placebo/no treatment Forearm blood flow 5 148 74 MD Random 68.80 (18.70, 118.90) Kanbay ADDIN EN.CITE 2014 General Allopurinol Placebo/no treatment Flow-mediated dilatation (%) 6 285 142 MD Fixed 2.75 (2.49, 3.01) Kanbay ADDIN EN.CITE 2014 General Allopurinol Placebo/no treatment Forearm blood flow (%) 5 130 71 MD Fixed 2.62 (2.32, 2.91) Kanbay ADDIN EN.CITE 2014 General Allopurinol Placebo/no treatment dilatation (%) 11 415 213 MD Fixed 2.69 (2.49, 2.89)
Chaudhari64 2012 Infants with encephalopathy Allopurinol Placebo/no treatment Seizures in neonatal period 3 114 58 RR Fixed 0.93 (0.75, 1.16) Agarwal ADDIN EN.CITE 2013 Patients with elevated SUA or kidney dysfunction Allopurinol Placebo/no treatment SBP (mmHg) 10 738 NA MD Random -3.33 (-5.25, NO ADDIN EN.CITE 65 (discordance in statistical significance) Bose ADDIN EN.CITE 2014 Patients with CKD or decreased kidney function Allopurinol Placebo/no treatment SBP (mmHg) 5 309 NA MD Random -2.70 (-7.30, 1.90) Agarwal ADDIN EN.CITE 2013 Patients with elevated SUA or kidney dysfunction Allopurinol Placebo/no treatment DBP (mmHg) 10 738 NA MD Random -1.29 (-2.48, NO ADDIN EN.CITE 65 (discordance in statistical significance) Bose ADDIN EN.CITE 2014 Patients with CKD or decreased kidney function Allopurinol Placebo/no treatment DBP (mmHg) 5 309 NA MD Random -1.90 (-4.90, 1.20)
Abbreviations: MA, meta-analysis; CKD, chronic kidney disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; MD, mean difference; SMD, standard mean difference; NA, not available. * Quantitative analyses were not performed, because we suspected some of the reported data misused standard error as standard deviation. Supplementary table S5 General characteristics and main findings of the 107 Mendelian randomisation studies* Author Year Population N/n Events (N studies)* Outcomes Genetic instruments (GI) SUA variance (R2) explained by GI Type of metric Estimate effect (95%CI) P value Concordance in overlapped MR Anthropometric variables 2016 UK 3,953 Appendicular lean mass (kg) rs737267 in SCL2A9 NA β 0.01 (NA, NA) 0.51 Lyngdoh ADDIN EN.CITE 2012 Switzerland 6,184 Fat mass (kg) rs6855911 in SCL2A9 3.2% β 0.05 (-0.10, 0.19) 0.52 Burgess ADDIN EN.CITE 2015 European 7,158 BMI (kg/m2) Genetic risk score of 29 SUA-related SNPs NA β -0.12(-0.53, 0.57 NO ADDIN EN.CITE (discordance in direction) Palmer ADDIN EN.CITE 2013 Danish 68,674 (2)* BMI (kg/m2) rs7442295 in SCL2A9 2.2% MD -0.04 (-0.25, 0.16) NA
Hughes ADDIN EN.CITE 2013 European 7,979 (2)* BMI (kg/m2) Genetic risk score of 5 SUA-related SNPs 2.3% β -0.05 (-0.12, 0.01) 0.11 Lyngdoh ADDIN EN.CITE 2012 Switzerland 6,184 BMI (kg/m2) rs6855911 in SCL2A9 3.2% β -0.01 (-0.16, 0.14) 0.94 Oikonen ADDIN EN.CITE 2012 Finnish (male) 1,985 BMI (kg/m2) rs13129697 in SCL2A9 NA β 0.04 (NA, NA) 0.82 Parsa ADDIN EN.CITE 2012 USA 868 BMI (kg/m2) rs16890979 in SCL2A9 NA MD 0.24 (-0.33, 0.81) 0.39 White ADDIN EN.CITE 2016 European 127,600 (64)* BMI (kg/m2) Genetic risk score of 31 SUA-related SNPs 4.2% MD§ -0.0003 (-0.0008, 0.0002) NA Lyngdoh ADDIN EN.CITE 2012 Switzerland 6,184 Waist circumference (cm) rs6855911 in SCL2A9 3.2% β 0.08 (-0.05, 0.24
Xiong ADDIN EN.CITE 2016 Chinese 1,667 BMD in femoral neck (g/cm2) Genetic risk score of 5 SUA-related SNPs 1.8% β 0.19 (-0.42, 0.81) 0.53 NO ADDIN EN.CITE 75 (discordance in direction) Dalbeth ADDIN EN.CITE 2015 USA 2,501 BMD in femoral neck (g/cm2) Genetic risk score of 5 SUA-related SNPs 3.3% β -0.27 (-0.58, 0.03) 0.08 Xiong ADDIN EN.CITE 2016 Chinese 1,667 BMD in L1–L4 (g/cm2) Genetic risk score of 5 SUA-related SNPs 1.8% β 0.39 (-0.26, 0.98) 0.26 Dalbeth ADDIN EN.CITE 2015 USA 2,501 BMD in spine (g/cm2) Genetic risk score of 5 SUA-related SNPs 3.3% β 0.08 (-0.32, 0.48) 0.68 Dalbeth ADDIN EN.CITE 2015 USA 2,501 BMD in total femur (g/cm2) Genetic risk score of 5 SUA-related SNPs 3.3% β -0.29 (-0.60, 0.01) 0.06
Xiong ADDIN EN.CITE 2016 Chinese 1,667 BMD in total hip (g/cm2) Genetic risk score of 5 SUA-related SNPs 1.8% β 0.19 (-0.36, 0.74) 0.50 Cardiovascular outcomes Kleber ADDIN EN.CITE 2015 Germany 3,060/444 Arrhythmia Genetic risk score of 8 SUA-related SNPs NA OR 0.98 (0.88, 1.08) 0.64 Kleber ADDIN EN.CITE 2015 Germany 3,060/368 Atrial fibrillation Genetic risk score of 8 SUA-related SNPs NA OR 1.03 (0.93, 1.15) 0.57 Kleber ADDIN EN.CITE 2015 Germany 3,060/316 Cardiomyopathy Genetic risk score of 8 SUA-related SNPs NA OR 1.00 (0.89, 1.12) 0.93 White ADDIN EN.CITE 2016 European 206,822/65,877 (58)* CHD Genetic risk score of 31 SUA-related SNPs 4.2% OR 1.05 (0.92, 1.20) 0.49 NO ADDIN EN.CITE
77-80 (discordance in direction) Keenan ADDIN EN.CITE 2016 Pakistan 122,776/54,501 (2)* Coronary heart disease Genetic risk score of 14 SUA-related SNPs 3.1% OR 1.02 (0.92, 1.12) 0.73 Kleber ADDIN EN.CITE 2015 Germany 3,060/2,418 Coronary artery disease (CAD) Genetic risk score of 8 SUA-related SNPs NA OR 0.99 (0.91, 1.09) 0.90 Han ADDIN EN.CITE 2015 Chinese 2,292/1,123 CHD rs11722228 in SLC2A9 NA OR 1.09 (0.88, 1.35) 0.43 rs4148152 in ABCG2 NA OR 0.84 (0.70, 1.11) 0.31 Yang ADDIN EN.CITE 2010 American 23,362/3,050 (5)* CHD incidence Genetic risk score of 8 SUA-related SNPs 6.0% OR 1.03 (0.85, 1.25) 0.76 Stark ADDIN EN.CITE 2009 Germany 2,714/1,473 CAD 10 SUA-related SNPs: NA OR Overall P>0.05 rs12129861 1.04 (0.93, 1.15) 0.54 rs780094 0.95 (0.85, 1.06) 0.39
rs734553 1.14 (1.00, 1.29) 0.06 rs734553 1.14 (0.96, 1.36) 0.13 rs742132 0.98 (0.87, 1.10) 0.74 rs1183201 0.96 (0.86, 1.07) 0.48 rs12356193 0.94 (0.81, 1.09) 0.42 rs17300741 1.08 (0.97, 1.21) 0.15 rs505802 1.04 (0.93, 1.17) 0.5 Keenan ADDIN EN.CITE 2016 Pakistan 22,926/4,526 (2)* Heart failure Genetic risk score of 14 SUA-related SNPs 3.1% OR 1.07 (0.88, 1.30) 0.51 Palmer ADDIN EN.CITE 2013 Danish 68,674/3,742 (2)* Ischemic heart disease rs7442295 in SCL2A9 2.2% HR 0.93 (0.79, 1.09) 0.38 Kleber ADDIN EN.CITE 2015 Germany 3,060/2,225 Hypertension Genetic risk score of 8 SUA-related SNPs NA OR 0.98 (0.90, 1.06) 0.56
Keenan ADDIN EN.CITE 2016 Pakistan 82,091/14,779 (2)* Ischemic stroke Genetic risk score of 14 SUA-related SNPs 3.1% OR 0.99 (0.88, 1.12) 0.93 Kleber ADDIN EN.CITE 2015 Germany 3,060/295 Peripheral vascular disease Genetic risk score of 8 SUA-related SNPs NA OR 0.92 (0.82, 1.04) 0.18 Kleber ADDIN EN.CITE 2015 Germany 3,060/538 Valve disease Genetic risk score of 8 SUA-related SNPs NA OR 1.08 (0.99, 1.19) 0.10 Yan ADDIN EN.CITE 2016 Chinese female T2DM patients 3,207 Diabetic macrovascular Genetic risk score of 3 SUA-related SNPs NA OR 1.18 (1.06, 1.33) 0.004 Oikonen ADDIN EN.CITE 2012 Finnish (male) 1,985 Carotid artery intima-media thickness (cIMT) (mm) rs13129697 in SCL2A9 NA β <0.0001 0.99 Mallamaci ADDIN EN.CITE 2015 Italian 449 cIMT (mm) rs734553 in SLC2A9 NA β 0.40 (NA, NA) <0.001
Mallamaci ADDIN EN.CITE 2015 Italian 449 Arterial stiffness (internal diameter) (mm) rs734553 in SLC2A9 NA β 0.48 (NA, NA) 0.003 White ADDIN EN.CITE 2016 European 89,667 (37)* DBP (mm Hg) Genetic risk score of 31 SUA-related SNPs 4.2% MD§ 0.005 (0.003, 0.007) NA NO ADDIN EN.CITE 70 72 73 79 83 70 72 73 79 83 84 (discordance in direction and statistical significance) Sedaghat ADDIN EN.CITE 2014 Netherlander 5,974 DBP (mm Hg) Genetic risk score of 30 SUA-related SNPs 4.2% β -0.42 (-0.72, -0.13) 0.01 Mallamaci ADDIN EN.CITE 2014 Italian 449 DBP (mm Hg) rs734553 in SCL2A9 NA MD NA 0.02 Palmer ADDIN EN.CITE 2013 Danish 68,674 (2)* DBP (mm Hg) rs7442295 in SCL2A9 2.2% MD 0.63 (-0.04, 1.29) NA
Hughes ADDIN EN.CITE 2013 European Caucasian 7,979 (2)* DBP (mm Hg) Genetic risk score of 5 SUA-related SNPs 2.3% β -0.002 (-0.13, 0.13) 0.97 Yang ADDIN EN.CITE 2010 American 20,699 (5)* DBP (mm Hg) Genetic risk score of 8 SUA-related SNPs 6.0% β -0.34 (-1.04, 0.35) 0.33 Parsa ADDIN EN.CITE 2012 USA 868 DBP-Clinic visit 1 (mm Hg) rs16890979 in SCL2A9 NA MD 0.52 (-0.62, 1.66) 0.36 Parsa ADDIN EN.CITE 2012 USA 868 DBP-High-salt 24-h (mm Hg) rs16890979 in SCL2A9 NA MD 0.42 (-0.56, 1.40) 0.41 Parsa ADDIN EN.CITE 2012 USA 868 DBP-Low-salt 24-h (mm Hg) rs16890979 in SCL2A9 NA MD 0.19 (-0.75, 1.13) 0.69
Parsa ADDIN EN.CITE 2012 USA 868 DBP-Salt sensitivity 24-h (mm Hg) rs16890979 in SCL2A9 NA MD -0.01 (-0.62, 0.60) 0.99 White ADDIN EN.CITE 2016 European 89,667 (37)* SBP (mm Hg) Genetic risk score of 31 SUA-related SNPs 4.2% MD§ 0.005 (0.003, 0.006) NA NO ADDIN EN.CITE 70 72 73 79 83 70 72 73 79 83 84 (discordance in direction and statistical significance) Sedaghat ADDIN EN.CITE 2014 Netherlander 5,974 SBP (mm Hg) Genetic risk score of 30 SUA-related SNPs 4.2% β -0.75 (-1.31, -0.19) 0.01 Mallamaci ADDIN EN.CITE 2014 Italian 449 SBP (mm Hg) rs734553 in SLC2A9 NA β NA 0.02 Palmer ADDIN EN.CITE 2013 Danish 68,674 (2)* SBP (mm Hg) rs7442295 in SCL2A9 2.2% MD 0.65 (-0.54, 1.85) NA
Hughes ADDIN EN.CITE 2013 European Caucasian 7,979 (2)* SBP (mm Hg) Genetic risk score of 5 SUA-related SNPs 2.3% β 0.07 (-0.12, 0.26) 0.47 Yang ADDIN EN.CITE 2010 American 20,673 (5)* SBP (mm Hg) Genetic risk score of 8 SUA-related SNPs 6.0% β -0.83 (-1.96, 0.30) 0.15 Parsa ADDIN EN.CITE 2012 USA 868 SBP-Clinic visit 1 (mm Hg) rs16890979 in SCL2A9 NA MD 0.08 (-1.70, 1.86) 0.38 Parsa ADDIN EN.CITE 2012 USA 868 SBP-High-salt 24-h (mm Hg) rs16890979 in SCL2A9 NA MD 2.20 (0.65, 3.75) 0.01 Parsa ADDIN EN.CITE 2012 USA 868 SBP-Low-salt 24-h (mm Hg) rs16890979 in SCL2A9 NA MD 1.48 (0.09, 2.87) 0.04 Parsa ADDIN EN.CITE 2012 USA 868 SBP-Salt sensitivity 24-h (mm Hg) rs16890979 in SCL2A9 NA MD 0.62 (-0.34, 1.58) 0.21
Sun ADDIN EN.CITE 2015 Chinese 5,198/2,999 T2DM 15 SUA-related SNPs NA OR No overall result rs12129861 1.03 (0.92, 1.16) 0.59 rs780094 1.22 (1.11, 1.35) rs2544390 0.97 (0.88, 1.06) 0.50 rs11722228 1.01 (0.91, 1.12) 0.83 rs16890979 0.98 (0.66, 1.45) 0.91 rs3775948 1.03 (0.93, 1.13) 0.59 rs10489070 0.96 (0.84, 1.10) 0.54 rs2231142 0.94 (0.85, 1.04) 0.21 rs742132 1.01 (0.91, 1.13) 0.80 rs1183201 0.98 (0.86, 1.11) 0.75 rs1165205 0.98 (0.87, 1.11) 0.75 rs1333049 1.024 (0.93, 1.12) 0.61 rs17300741 0.97 (0.80, 1.19) 0.78 rs506338 0.99 (0.89, 1.10) 0.87
72 79 92 93 (discordance in direction and statistical significance) Parsa ADDIN EN.CITE 2012 USA 868 eGFR (mL/min/1.73 m2) rs16890979 in SCL2A9 NA MD 0.42 (-1.78, 2.62) 0.71 Yang ADDIN EN.CITE 2010 American 23,844 (5)* Log eGFR (mL/min/1.73 m2) Genetic risk score of 8 SUA-related SNPs 6.0% β 0.001 (-0.01, 0.02) 0.91 Tabara ADDIN EN.CITE 2010 Japanese 5,165 (2)* eGFR (mL/min/1.73 m2) Genetic risk score of 3 SUA-related SNPs NA β -0.11 (NA, NA) <0.001 Voruganti ADDIN EN.CITE 2014 American Indians 3,604 (3)* eGFR (mL/min/1.73 m2) 7 SNPs in SCL2A9: 5.3% Residual variance¶ No overall result rs16890979 0.52 (NA, NA) 0.002 rs6832439 0.52 (NA, NA) 0.002 rs6449213 0.22 (NA, NA) 0.08 rs13131257 0.58 (NA, NA) 0.001 rs737267 0.44 (NA, NA) 0.004
rs10805346 0.69 (NA, NA) <0.001 rs12498956 0.24 (NA, NA) 0.05 Voruganti ADDIN EN.CITE 2014 American Indians 3,604 (3)* SCr (mmol/L) 7 SNPs in SCL2A9: 5.3% Residual variance¶ No overall result NO ADDIN EN.CITE 93 (discordance in statistical significance) rs16890979 0.53 (NA, NA) 0.001 rs6832439 0.54 (NA, NA) 0.002 rs6449213 0.27 (NA, NA) 0.003 rs13131257 0.60 (NA, NA) 0.000 rs737267 0.46 (NA, NA) 0.004 rs10805346 0.68 (NA, NA) 0.000 rs12498956 0.23 (NA, NA) 0.06 Hughes ADDIN EN.CITE 2013 European Caucasian 7,979 (2)* SCr (mmol/L) Genetic risk score of 5 SUA-related SNPs 2.3% β -19.23 (-40.32, 1.86) 0.07 Voruganti ADDIN EN.CITE 2014 American Indians 3,604 (3)* Albumin/creatinine ratio 7 SNPs in SCL2A9: 5.3% Residual variance¶ Overall P>0.05 rs16890979 0.13 (NA, NA) 0.07 rs6832439 0.16 (NA, NA) 0.05 rs6449213 0.01 (NA, NA) 0.64
rs13131257 0.14 (NA, NA) 0.05 rs737267 0.14 (NA, NA) 0.06 rs10805346 0.14 (NA, NA) 0.10 rs12498956 0.07 (NA, NA) 0.15 All-cause and cause-specific mortality Kleber ADDIN EN.CITE 2015 Germany 3,060/na Cardiovascular mortality Genetic risk score of 8 SUA-related SNPs NA aHR 1.11 (1.02, 1.21) 0.02 Kleber ADDIN EN.CITE 2015 Germany 3,060/na All-cause mortality Genetic risk score of 8 SUA-related SNPs NA aHR 1.02 (0.95, 1.09) 0.59 Kleber ADDIN EN.CITE 2015 Germany 3,060/na Sudden cardiac death Genetic risk score of 8 SUA-related SNPs NA aHR 1.18 (1.03, 1.35) 0.02 Metabolites White ADDIN EN.CITE 2016 European 196,621 (68)* HDL-C (mmol/L) Genetic risk score of 31 SUA-related SNPs 4.2% MD§ -0.008 (-0.010, -0.006) NA
White ADDIN EN.CITE 2016 European 196,621 (68)* LDL-C (mmol/L) Genetic risk score of 31 SUA-related SNPs 4.2% MD§ -0.001 (-0.003, 0.001) NA White ADDIN EN.CITE 2016 European 196,621 (68)* TC (mmol/L) Genetic risk score of 31 SUA-related SNPs 4.2% MD§ 0.000 (-0.002, 0.002) NA White ADDIN EN.CITE 2016 European 196,621 (68)* TG (mmol/L) Genetic risk score of 31 SUA-related SNPs 4.2% MD§ 0.014 (0.013, 0.016) NA NO ADDIN EN.CITE 73 73 94 (discordance in direction) Rasheed ADDIN EN.CITE 2014 European 8,208 (2)* TG (mmol/L) Genetic risk score of 5 SUA-related SNPs 1.7% β −1.01 (-2.57, 0.56) 0.21 Parsa ADDIN EN.CITE 2012 USA 868 TG (mmol/L) rs16890979 in SCL2A9 NA MD 2.38 (-2.87, 7.63) 0.35
Xiong ADDIN EN.CITE 2016 Chinese 1,667 Parathyroid hormone (pg/mL) Genetic risk score of 5 SUA-related SNPs 1.8% β -0.63 (-2.12, 0.85) 0.40 Xiong ADDIN EN.CITE 2016 Chinese 1,667 Phosphorus (mmol/L) Genetic risk score of 5 SUA-related SNPs 1.8% β -0.16 (-0.74, 0.42) 0.59 Burgess ADDIN EN.CITE 2015 European 7,158 C-reactive protein (CRP) (mg/L) Genetic risk score of 29 SUA-related SNPs NA β -0.05 (-0.15, 0.05) 0.37 Xiong ADDIN EN.CITE 2016 Chinese 1,667 Calcium (mmol/L) Genetic risk score of 5 SUA-related SNPs 1.8% β 0.06 (-0.10, 0.21) 0.48 Xiong ADDIN EN.CITE 2016 Chinese 1,667 Tropocollagen type 1 N-terminal propeptide (ng/L) Genetic risk score of 5 SUA-related SNPs 1.8% β 0.11 (-1.53, 1.75) 0.90
Xiong ADDIN EN.CITE 2016 Chinese 1,667 β-crosslaps of type I collagen containing cross-linked Ctelopeptide (ng/L) Genetic risk score of 5 SUA-related SNPs 1.8% β -1.45 (-3.17, 0.27) 0.10 Xiong ADDIN EN.CITE 2016 Chinese 1,667 25(OH)D (ng/mL) Genetic risk score of 5 SUA-related SNPs 1.8% β 0.76 (-0.63, 2.15) 0.28 Neurocognitive disorders ADDIN EN.CITE 2014 Spain 343 Dementia in PD Genetic risk score of 8 SUA-related SNPs NA OR 1.05 (0.70, 3.00) 0.31 NO ADDIN EN.CITE (discordance in direction and statistical significance) Simon ADDIN EN.CITE 2014 USA 808 (2)* PD progression Genetic risk score of 3 SNPs in SCL2A9 NA HR 1.16 (1.00, 1.35) 0.06 Gao97 2013 American 1,699 Parkinson’s disease 12 SNPs in SCL2A9 NA OR Overall P>0.05 rs16890979 1.06 (0.90, 1.24) 0.51 rs13129697 0.99 (0.85, 1.16) 0.91
rs737267 1.01 (0.86, 1.18) 0.91 rs6855911 1.00 (0.85, 1.18) 0.98 rs4697700 1.03 (0.88, 1.22) 0.69 rs4481233 1.01 (0.85, 1.21) 0.90 rs7442295 1.06 (0.90, 1.26) 0.50 rs6449213 1.01 (0.85, 1.21) 0.88 rs1014290 1.04 (0.88, 1.22) 0.67 rs12509955 0.99 (0.84, 1.18) 0.93 rs17251963 1.05 (0.88, 1.25) 0.59 rs12510549 0.96 (0.81, 1.14) 0.65 ADDIN EN.CITE 2013 UK 1,061 Parkinson’s disease Genetic risk score of 9 SUA-related SNPs NA OR 1.55 (1.10, 2.18) 0.01 Facheris ADDIN EN.CITE 2011 European 664 (3)* Age at onset of PD 4 SNPs in SCL2A9 NA β Null after multiple testing correction rs737267 NA 3.10 (0.17, 6.03) 0.04 rs6449213 NA -1.18 (-4.96, 2.59) 0.54
rs1014290 NA -4.56 (-8.13, -1.00) 0.01 rs733175 NA 3.59 (0.67, 6.51) 0.02 Lyngdoh ADDIN EN.CITE 2013 Switzerland 3,716/660 Lifetime anxiety disorders rs6855911 in SLC2A9 3.2% OR (male) 1.40 (1.07, 1.84) 0.02 OR (female) 0.97 (0.80, 1.17) 0.73 Lyngdoh ADDIN EN.CITE 2013 Switzerland 3,716/370 Current anxiety disorders rs6855911 in SLC2A9 3.2% OR (male) 1.42 (0.99, 2.03) 0.06 OR (female) 0.84 (0.66, 1.06) 0.14 Houlihan ADDIN EN.CITE 2010 European (Population 1: LBC1936) 1,091 Memory performance 4 SNPs in SCL2A9 NA β Overall P<0.05 NO ADDIN EN.CITE (discordance in statistical significance) rs733175 -0.10 (NA, NA) rs1014290 -0.07 (NA, NA) 0.01 rs6449213 -0.07 (NA, NA) 0.01 rs6449213 -0.07 (NA, NA) 0.01 Houlihan ADDIN EN.CITE 2010 European (Population 2: ET2DS) 1,066 Memory performance 4 SNPs in SCL2A9 NA β Overall P>0.05 rs733175 -0.03 (NA, NA) 0.27 rs1014290 -0.04 (NA, NA) 0.22
rs6449213 -0.03 (NA, NA) 0.41 rs6449213 -0.04 (NA, NA) 0.19 Other outcomes Kleber ADDIN EN.CITE 2015 Germany 3,060/226 Cancer Genetic risk score of 8 SUA-related SNPs NA OR 0.95 (0.83, 1.08) 0.41 Keenan ADDIN EN.CITE 2016 Pakistan 71,501/3,151 (2)* Gout Genetic risk score of 14 SUA-related SNPs 3.1% OR 5.84 (4.56,0 7.49) NO ADDIN EN.CITE 77 79 (discordance in statistical significance) Kleber ADDIN EN.CITE 2015 Germany 3,060/19 Gout Genetic risk score of 8 SUA-related SNPs NA OR 1.15 (0.72, 1.82) 0.56 Yang ADDIN EN.CITE 2010 American 25,982/1,033 (5)* Gout Genetic risk score of 8 SUA-related SNPs 6.0% OR 12.40 (8.50, 18.00) Abbreviations: MR, Mendelian randomisation study; BMI, body mass index; BMD, bone mineral density; SBP, systolic blood pressure; DBP, diastolic blood pressure; CHD, coronary heart disease; IMT, intima-media thickness; CVD, cardiovascular disease; T2DM, Type 2 diabetes; CKD, chronic kidney disease; SCr, serum creatinine; eGFR, glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C,