Elevated Serum Uric Acid Increases Risks for Developing High LDL Cholesterol and Hypertriglyceridemia A five-year Cohort Study in Japan

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Accepted Manuscript
Elevated serum uric acid increases risks for developing high LDL
cholesterol and hypertriglyceridemia: A five-year cohort study in
Japan
Masanari Kuwabara, Claudio Borghi, Arrigo F.G. Cicero, Ichiro
Hisatome, Koichiro Niwa, Minoru Ohno, Richard J. Johnson,
Miguel A. Lanaspa
PII: S0167-5273(17)37927-5
DOI: doi:10.1016/j.ijcard.2018.03.045
Reference: IJCA 26174
To appear in:
Received date: 22 December 2017
Revised date: 25 February 2018
Accepted date: 9 March 2018
Please cite this article as: Masanari Kuwabara, Claudio Borghi, Arrigo F.G. Cicero,
Ichiro Hisatome, Koichiro Niwa, Minoru Ohno, Richard J. Johnson, Miguel A. Lanaspa
, Elevated serum uric acid increases risks for developing high LDL cholesterol and
hypertriglyceridemia: A five-year cohort study in Japan. The address for the corresponding
author was captured as affiliation for all authors. Please check if appropriate. Ijca(2017),
doi:10.1016/j.ijcard.2018.03.045
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Elevated Serum Uric Acid Increases Risks for Developing High LDL Cholesterol and 
Hypertriglyceridemia: A five-year Cohort Study in Japan 
 Short title: Uric acid and LDL cholesterol 
Masanari Kuwabara, MD, PhD
1,2,3
, Claudio Borghi, MD, PhD
4
, Arrigo FG Cicero, MD, 
PhD
4
, Ichiro Hisatome, MD, PhD
5
, Koichiro Niwa, MD
3
, Minoru Ohno, MD, PhD
2
, 
Richard J Johnson, MD
1
, Miguel A Lanaspa, DVM, PhD
1 
 
1
Division of Renal Diseases and Hypertension, School of Medicine, University of Colorado 
Denver, CO, USA; 
2
Department of Cardiology, Toranomon Hospital, Tokyo, Japan; 
3
Cardiovascular Center, St. Luke’s International Hospital, Tokyo, Japan; 
4
Medical and Surgical Sciences Department, University of Bologna, Italy 
5
Division of Regenerative Medicine and Therapeutics, Tottori University Graduate School 
of Medical Sciences, Yonago, Japan 
 
Corresponding author and contact details: Masanari Kuwabara, MD, PhD 
Division of Renal Diseases and Hypertension, School of Medicine, University of Colorado 
Denver 
Mail Stop C281, 12700 East 19
th
 Avenue, Aurora, CO 80045, the United States of America 
Phone: 303-724-4852; Fax: 303-724-4868; E-mail: kuwamasa728@gmail.com 
 
Acknowledgement of grant support: The authors thank the patients and all staff in Center 
for Preventive Medicine, St. Luke's International Hospital, for assistance with data 
collection. Dr. Kuwabara reports the grant for studying abroad from Federation of National 
Public Service Personnel Mutual Aid Association in Japan. This study has no grant support. 
 
Conflicts of interest: Dr. Johnson has equity with XORT Therapeutics that is developing 
novel xanthine oxidase inhibitors and with Colorado Research Partners LLC that is 
developing inhibitors of fructose metabolism. In addition, Dr. Johnson is an inventor on 
several patents licensed to XORT Therapeutics. (US Patent No 7,799,794, US Patent No. 
8,557,831). 
 
Keywords: Uric acid; Epidemiology; risk factor; low-density lipoprotein cholesterol; 
Hypertriglyceridemia 
 
Word counts: Abstract 250 words; Text 2,421 words; Figures 2; Tables 2; References 42; 
Supplementary material 1 
 
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Abstract 
Background: High serum uric acid (SUA) is associated with the dyslipidemia, but whether 
hyperuricemia predicts an increase in serum low-density lipoprotein (LDL) cholesterol is 
unknown. This study is to evaluate whether an elevated SUA predicts the development of 
high LDL cholesterol as well as hypertriglyceridemia. 
Methods: This is a retrospective 5-year cohort study of 6,476 healthy Japanese adults (age, 
45.7±10.1 years; 2.243 men) who underwent health examinations at 2004 and were 
reevaluated in 2009 at St. Luke's International Hospital, Tokyo, Japan. Subjects were 
included if at their baseline examination they did not have hypertension, diabetes mellitus, 
dyslipidemia, chronic kidney disease, or if they were on medication for hyperuricemia 
and/or gout. The analysis was adjusted for age, body mass index (BMI), smoking and 
drinking habits, baseline estimated glomerular filtration rate (eGFR), baseline SUA and 
SUA change over the 5 years. 
Results: High baseline SUA was an independent risk for developing high LDL cholesterol 
both in men (OR: 1.159 per 1 mg/dl increase, 95% CI:1.009-1.331) and women (OR: 1.215, 
95% CI:1.061-1.390). Other risk factors included a higher baseline LDL cholesterol, higher 
BMI, and higher baseline eGFR (the latter two in women only). Increased SUA over 5 
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years were also independent risks for developing high LDL cholesterol and 
hypertriglyceridemia, but not for low high-density lipoprotein (HDL) cholesterol. 
Conclusions: This is the first study to report that an elevated SUA increases the risk for 
developing high LDL cholesterol, as well as hypertriglyceridemia. This may shed light into 
the role of SUA in cardiovascular disease. 
 
 
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Introduction 
High low-density lipoprotein (LDL) cholesterol is a strong risk factor for cardiovascular 
diseases.[1] Targeting high LDL cholesterol is one of the most important therapeutic 
approaches to prevent atherosclerotic cardiovascular diseases.[2] Therefore, to identify the 
risk factors for high LDL cholesterol is clinically relevant. Several epidemiological studies 
demonstrate a significant association between serum uric acid (SUA) and metabolic 
syndrome, high body mass index or waist circumference, high fasting blood glucose, and 
dyslipidemia.[3, 4] Moreover, some studies showed that hyperuricemia is primarily 
associated with hypertriglyceridemia and low high-density lipoprotein (HDL) cholesterol in 
cross-sectional studies.[5-7] However, there is no reports on whether the presence of 
hyperuricemia predicts the development of high LDL cholesterol. In this study we tested 
the hypothesis that an elevated SUA can predict the development of high LDL cholesterol, 
as well as hypertriglyceridemia in a healthy adult population from Japan. 
 
Methods 
Study design and study subjects 
This is a large-scale, single-center, retrospective cohort study to detect whether an elevated 
SUA is a risk factor for developing high LDL cholesterol and hypertriglyceridemia. We 
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used the database at the Center for Preventive Medicine, St. Luke's International Hospital, 
Tokyo, Japan. The medical records of subjects in this study, who underwent annual medical 
examination at the hospital from 2004 to 2009, were analyzed. When the subjects in this 
study had more than one annual exam, we only used the first record of that year to avoid 
double counts. Some studies of this cohort data base have been previously published.[4, 
8-14] 
 
Inclusion and exclusion criteria 
We included subjects between 30 and 85 years of age at the baseline (2004). We excluded 
subjects with baseline hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease 
(CKD), orwho were on medication for hyperuricemia and/or gout at study entry (Figure 1). 
We also excluded subjects on medication for hypertension, diabetes mellitus, and 
dyslipidemia at the baseline. The exclusion of subjects with hypertension, diabetes mellitus 
and CKD was performed as these conditions or their treatments (e. thiazides) may affect 
serum lipids and/or SUA. 
 
Study outcomes 
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We analyzed risk factors for developing each component of dyslipidemia: 1) high LDL 
cholesterol (≥140 mg/dL), 2) low HDL cholesterol (<40 mg/dL), and 3) 
hypertriglyceridemia (triglyceride ≥150 mg/dL)[15], over 5 years by multivariable 
regression analyses with the adjustments for age, body mass index (BMI), smoking and 
drinking habits, baseline SUA levels, SUA change over 5 years, and each component of 
dyslipidemia (LDL cholesterol, HDL cholesterol, or triglyceride). All analyses were 
stratified by sex due to the differences in SUA levels in men and women. 
 
Definition of hypertension, diabetes mellitus, CKD, and hyperuricemia 
An elevated LDL cholesterol was defined as ≥140 mg/dl, HDL cholesterol as <40 mg/dL, 
and triglycerides as ≥150 mg/dL.[15] We directly measured LDL cholesterol in our 
laboratory and Friedewald formula was not used. Hypertension was defined as being on 
antihypertensive medication and/or systolic blood pressure (BP) of ≥ 140 mmHg and/or 
diastolic BP of ≥ 90 mmHg. BP readings were obtained using an automatic brachial 
sphygmomanometer. Diabetes mellitus status was defined by current history of diabetes 
mellitus and/or glycated hemoglobin (HbA1c) (National Glycohemoglobin Standardization 
Program (NGSP)) of ≥ 6.5% according to International Expert Committee.[16]. CKD was 
defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m
2 
using the 
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Japanese GFR equation: eGFR (mL/min/1.73m
2
) = 194 × serum creatinine-1.094 × 
age-0.287 (×0.739 if female).[17] Hyperuricemia was defined as >7.0 mg/dL of SUA in 
men and ≥6.0 mg/dL in women.[18-21] SUA change over 5 years was defined as the 
following formula: 
SUA change = (SUA levels in 2009) – (SUA levels in 2004). 
 
Statistical analysis 
All statistical analyses were performed using the SPSS Statistics software (IBM SPSS 
Statistics version 22 for Windows; IBM, New York). The statistically significant level was 
set as at α = 0.05, and all statistical analyses were two-sided. Data are expressed as mean ± 
standard derivation (SD) or as percent frequency. Comparisons between two groups were 
performed with t-tests for normally distributed variables and χ2 analyses for categorical data. 
The risk factors for developing each component of dyslipidemia; 1) high LDL cholesterol, 
2) low HDL cholesterol, and 3) hypertriglyceridemia, were evaluated by univariate and 
multivariable logistic regression models with adjustments for age, BMI, smoking and 
drinking habits, baseline eGFR, baseline SUA, SUA change over 5 years, and each 
component of dyslipidemia (baseline LDL cholesterol, HDL cholesterol, or triglycerides in 
each model). Each odds ratio (OR) for developing high LDL cholesterol and 
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hypertriglyceridemia over 5 years were also calculated. Due to sex-difference in SUA 
distribution, all the analyses were stratified by sex. 
 
Ethical considerations 
We adhered to the principles of the Declaration of Helsinki. All data were collected as 
individual data were anonymous without identifiable personal information. St. Luke’s 
International Hospital Ethics Committee approved the protocol for this study. Informed 
consent was obtained from all the subjects. 
 
Results 
Study characteristics 
There were 13,201 subjects who underwent annual medical examination at the center both 
in 2004 (baseline) and in 2009 (followed over 5 years). We excluded 121 subjects who 
were younger than 30 years old and 10 subjects who were 85 years or older in 2004 
because subjects younger than 30 years had low risk for cardiometabolic diseases and 
subjects over 85 years carry a high mortality. Out of 13,070 subjects between 30 and 85 
years of age in 2004, we excluded 2,599 subjects with hypertension, 575 subjects with 
diabetes mellitus, 5,118 subjects with preexisting dyslipidemia, 494 subjects with CKD, 
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and 373 subjects who had medication for hyperuricemia and/or gout in 2004. Some 
subjects had two or more diseases in 2004. Finally, 6,476 subjects were included in the 
analyses (Figure 1). Baseline demographic data are shown by sex and presence/absence of 
hyperuricemia in Table 1. Baseline SUA levels were different between men and women 
(6.00±1.16 mg/dL vs. 4.29±0.86 mg/dL, p<0.001). 
 
Risk factor for developing high LDL cholesterol, low HDL cholesterol, and 
hypertriglyceridemia 
We analyzed the risk for developing high LDL cholesterol, low HDL cholesterol, and 
hypertriglyceridemia (Table 2). The mean cumulative incidences of high LDL cholesterol, 
low HDL cholesterol, and hypertriglyceridemia over 5years were 11.7% (262/2,243), 1.8% 
(41/2,243), and 9.7% (217/2,243) in men and 12.6% (535/4,233), 0.28% (12/4,233), and 
2.0% (86/4,233) in women, respectively. Overall, the mean cumulative incidence of 
dyslipidemia over 5 years was 21.0% in men and 15.0% in women. When stratified by each 
1 mg/dL of SUA levels, SUA levels was positively correlated with cumulative incidences 
of dyslipidemia over 5 years both in men (R=0.96, p=0.001) and women (R=0.94, p<0.001) 
by Pearson’s correlation coefficient (Figure 2). 
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Crude (non-adjusted) analysis showed baseline higher SUA was a risk for 
developing hypertriglyceridemia both in men and women, high LDL cholesterol in women, 
and low HDL cholesterol in men. After multiple adjustments, including adjustment of 
baseline LDL cholesterol, HDL cholesterol, or triglycerides for each model, a higher 
baseline SUA levels and increased SUA over 5 years were independent risk factors for 
developing high LDL cholesterol in men (OR per 1 mg/dL increase: 1.159, 95% CI: 
1.009-1.331; SUA change over 5 years, OR per 1 mg/dL increase: 1.709, 95% CI: 
1.401-2.084) and women (OR: 1.215, 95% CI: 1.061-1.390; SUA change over 5 years, OR: 
2.031, 95% CI: 1.700-2.426). Other risk factors for developing high LDL cholesterol were 
higher baseline LDL cholesterol both in men and women, and higher BMI and higher 
baseline eGFR in women (Table 2, High LDL cholesterol). After multiple adjustments, 
higher baseline SUA and increased SUA over 5 years were also independent risk factors for 
developing hypertriglyceridemia both in men (baseline SUA, OR: 1.370, 95% CI: 
1.179-1.591; SUA change over 5 years, OR: 1.517, 95% CI: 1.244-1.850) and women 
(baseline SUA, OR: 1.942, 95% CI: 1.462-2.578; SUA change over 5 years, OR: 2.219, 
95% CI: 1.578-3.121), as well as younger age and higher baseline triglycerides both in men 
and women, smoking habits in men, and lower baseline eGFR in women (Table 2, 
Hypertriglyceridemia). However, higher baseline SUA and increased SUA over 5 years 
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were not risk factors for developing low HDL cholesterol both in men and women. Only 
lower baseline HDL cholesterol was a risk for developing low HDL cholesterol both in men 
and women (Table 2, Low HDL cholesterol).Risk factors for developing hyperuricemia 
Additionally, we checked the risk factors for developing hyperuricemia over five years. In 
this analysis, we excluded 2,307 baseline hyperuricemic subjects (1,835 men) from 13,070 
subjects at the entry. Of 10,763 subjects, 676 subjects (427 men) had hyperuricemia over 5 
years. We checked the risk factors for developing hyperuricemia over 5 years after multiple 
adjustments with age, sex, BMI, smoking and drinking habits, hypertension, diabetes 
mellitus, CKD, LDL cholesterol, HDL cholesterol, and triglyceride. After multiple 
adjustments, the risk factors for developing hyperuricemia over 5 years are younger age 
(OR per 1 year increase: 0.987, 95% CI: 0.979-0.995), men (OR: 1.263, 95% 
CI:1.019-1.567), larger BMI (OR:1.092, 95% CI:1.061-1.125), smoking (OR: 1.246, 95% 
CI: 1.038-1.496), drinking habits (OR: 1.443. 95% CI: 1.207-1.725), hypertension (OR: 
1.977, 95% CI:1.623-2.407), CKD (OR:3.169, 95% CI:2.198-4.571), and higher 
triglyceride (OR: 1.003 per 1 mg/dL increase: 1.003, 95% CI: 1.002-1.003), but not 
diabetes mellitus (Supplementary Table S1). 
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Discussion 
In previous studies, hyperuricemia is associated with hypertriglyceridemia and low HDL 
cholesterol, and is also highly predictive of metabolic syndrome, but whether a high SUA 
predicts a rise in LDL cholesterol has, to our knowledge, never been examined. Here we 
examined a healthy Japanese adult population with a mean BMI of 22 to 23 in which we 
excluded baseline hypertension, diabetes mellitus, dyslipidemia and CKD. The primary 
finding was that a high SUA at baseline predicted an elevated LDL cholesterol, and the risk 
for developing an elevated LDL cholesterol was 16% in men and 22% in women for each 1 
mg/dL increase of baseline SUA. Change in SUA levels over the 5 years was also a risk 
factor for elevated LDL cholesterol, with an even greater OR (1.71 in men and 2.03 in 
women for 1 mg/dl SUA change). 
These findings do not document a causal role for hyperuricemia in raising serum 
cholesterol, but are consistent with findings that SUA may have a role in lipogenesis and in 
blocking fatty acid oxidation.[22-24] While outside the scope of this study, several 
potential mechanisms could be taking place that explains a deleterious causal role of uric 
acid for dyslipidemia. For example, even though uric acid is commonly considered an 
antioxidant, we and others have shown that at high concentrations, uric acid acts as a 
pro-oxidant molecule. More specifically, high intracellular uric acid levels have been 
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shown to induce mitochondrial translocation of the nicotinamide adenine dinucleotide 
phosphate (NADPH) oxidase subunit, NADPH oxidase 4 (Nox4), thus leading to increased 
mitochondrial oxidative stress, mitochondrial dysfunction and citrate release to the cytosol 
for de novo lipogenesis and triglyceride synthesis.[22] Furthermore, xanthine oxidase 
mediated conversion of hypoxanthine/xanthine to uric acid is associated with the generation 
of oxidants,[25] especially hydrogen peroxide[26] and uric acid is able to form reactive 
intermediates including alkylating species by reacting with peroxynitrite.[27] Also, we and 
others have shown that both soluble and crystallized uric acid inhibits AMP-Kinase leading 
to reduced ability for fatty acid oxidation and triglyceride accumulation.[28-30] Other 
potential mechanisms have been proposed to explain how SUA can modulate LDL 
cholesterol levels. For example, Minami et al. proposed that higher SUA levels 
significantly correlate with increased lipid peroxidation rates which are ameliorated by the 
xanthine oxidase inhibitor, allopurinol[31] and a critical role for SUA in inhibiting 
lipoprotein lipase activity in endothelial cells has also been suggested.[32] Nevertheless, 
despite increasing evidence in basic research, the accurate mechanism how SUA increases 
LDL cholesterol and triglyceride is still unclear. 
 Whether reducing SUA levels can improve LDL cholesterol and triglyceride levels 
is controversial. One meta-analysis reported that reducing SUA lowering therapy with 
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xanthine oxidase inhibitor like allopurinol did not improve serum lipid levels, and in fact 
was associated with a reduction in HDL cholesterol.[33] However, all of the studies 
analyzed by the meta-analysis were short term (4 to 24 weeks)[34-40] and longer and 
higher quality studies are warranted.[33] Indeed, one three year study reported that 
allopurinol led to significant improvement in HDL cholesterol and serum triglycerides 
compared to the control group.[41] A recent longitudinal study showed that high SUA 
levels increased the risk of hypertriglyceridemia over 8 years of follow-up.[42] The study is 
longer assessed than our study with SUA quartiles, but our study assessed the continuous 
value of SUA. The results look similar, but our study adjusted SUA change over 5 years 
and showed that elevated SUA increased the risk for not only hypertriglyceridemia but also 
high LDL cholesterol, which is a new discovery. 
Our studies did not show any significant relationship of SUA with HDL-cholesterol 
level following multivariable analysis. In contrast, our present study showed that high 
levels of SUA was an independent predictor for the development of high LDL-cholesterol 
and hypertriglyceridemia. The difference between these observations may relate to the 
consequence of the length of the study, as ours extended over a 5 year period as opposed to 
short term studies of weeks or months. 
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Our study carries some limitations. First, the study population may have a selection 
bias because it is a retrospective single-center study, but there is a positive aspect that every 
examination was done in the same laboratory. The retrospective nature of this study has a 
limitation to reach final conclusions that increased SUA over 5 years is an independent risk 
factor for developing high LDL cholesterol and hypertriglyceridemia. Our observation 
study could show just the associations. We need to conduct a prospective study to show 
whether SUA becomes an independent risk factor for developing high LDL cholesterol and 
hypertriglyceridemia. Second, this study did not assess causes of secondary dyslipidemia, 
like thyroid function and alcohol. Third, the number of subjects with hyperuricemia was 
much smaller than those without hyperuricemia because we excluded the subjects with 
hyperuricemia and/or gout on medication at the baseline. However, we evaluated more than 
400 men and around 150 women with hyperuricemia, which suggests that accurate analysis 
could be conducted after multiple adjustments. Fourth, our longitudinal study is also 
subject to random error and therefore our findings could be partially explained by 
regression to the mean. Finally, our study is an observational study, and interventional 
studies are needed to clarify the treatment for hyperuricemia is useful to prevent 
dyslipidemia and cardiovascular diseases. 
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In conclusion, a high baseline SUA level as well as an increase in SUA over 5 years 
is strongly associated with developing high LDL cholesterol and hypertriglyceridemia. 
Asymptomatic hyperuricemia should be considered by clinical practitioners as potentially 
important risks for the development and progression of high LDL cholesteroland 
hypertriglyceridemia and thus, cardiovascular disease. 
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Acknowledgements 
All the authors of this paper fulfill the criteria of authorship. The authors thank all staff in 
Center for Preventive Medicine, St. Luke's International Hospital, for assistance with data 
collection. Dr. Kuwabara reports the grant for studying abroad from Federation of National 
Public Service Personnel Mutual Aid Association in Japan. 
 
Source of funding 
None 
 
Conflict of Interest/ Disclosures 
Dr. Johnson has equity with XORT Therapeutics that is developing novel xanthine oxidase 
inhibitors and with Colorado Research Partners LLC that is developing inhibitors of 
fructose metabolism. In addition, Dr. Johnson is an inventor on several patents licensed to 
XORT Therapeutics. (US Patent No 7,799,794, US Patent No. 8,557,831). The remaining 
authors have nothing to disclose. 
 
 
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Tables 
Table 1. Study subjects’ demographic data by sex between hyperuricemia and normouricemia 
 
Men 
 
Women 
 
Normouricemia 
Hyperuricemia 
(SUA >7.0 mg/dL) 
p 
 
Normouricemia 
Hyperuricemia 
(SUA ≥6.0 mg/dL) 
P 
Number of subjects 1,842 401 
 
4,087 146 
Age 49.3±11.3 47.5±10.1 0.001 
 
45.5±9.3 52.3±10.9 <0.001 
Height (cm) 170.5±6.1 170.6±6.0 0.77 
 
158.4±5.4 157.2±5.9 0.006 
Weight (kg) 65.4±8.5 69.1±9.1 <0.001 
 
51.3±6.5 53.3±8.4 0.006 
Body mass index (kg/m
2
) 22.4±2.5 23.7±2.8 <0.001 
 
20.5±2.4 21.6±3.1 <0.001 
Smoking 57.5% 62.6% 0.065 
 
17.3% 27.4% 0.008 
Drinking habits 62.2% 70.8% 0.001 
 
30.2% 44.5% <0.001 
Systolic BP (mmHg) 115.3±12.2 117.1±11.1 0.003 
 
108.0±12.5 112.8±13.6 <0.001 
Diastolic BP (mmHg) 72.3±8.2 73.6±7.4 0.002 
 
67.1±8.4 69.5±9.0 <0.001 
Pulse rate (bpm) 69.7±9.4 70.9±9.7 0.022 
 
74.4±10.2 73.2±9.9 0.16 
Fasting blood glucose (g/dL) 99.5±8.2 100.7±9.1 0.008 93.2±6.8 95.9±7.9 <0.001 
HbA1c (%) 4.92±0.33 4.95±0.33 0.11 4.87±0.32 4.97±0.35 <0.001 
Total cholesterol (mg/dL) 188.9±23.0 190.3±24.4 0.28 
 
192.6±26.3 199.4±23.3 0.002 
LDL cholesterol (mg/dL) 108.4±19.7 109.8±19.8 0.20 
 
102.9±20.7 108.4±20.1 0.001 
HDL cholesterol (mg/dL) 61.0±12.9 59.2±13.7 0.015 
 
72.1±14.3 70.9±14.4 0.31 
Triglyceride (mg/dL) 79.9±27.6 91.0±30.5 <0.001 
 
61.3±23.6 72.4±25.0 <0.001 
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eGFR (mL/min/1.73m
2
) 86.5±13.7 82.3±12.2 <0.001 
 
91.2±15.0 81.7±14.2 <0.001 
Serum uric acid (mg/dL) 5.63±0.90 7.69±0.56 <0.001 
 
4.22±0.77 6.44±0.41 <0.001 
Serum uric acid change (mg/dL) 0.03±0.79 -0.70±0.94 <0.001 
 
0.07±0.60 -0.55±0.71 <0.001 
BP, blood pressure; bpm, beats per minute; HbA1c, glycated hemoglobin; LDL, low-density lipoprotein; HDL, high-density lipoprotein; 
eGFR, estimated glomerular filtration rate; SUA, serum uric acid 
Data are presented as mean  standard deviation. 
 
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Table 2. Risk factors for developing a) high LDL cholesterol, b) low HDL cholesterol, and c) hypertriglyceridemia over 5 years 
a)High LDL cholesterol 
 
 Crude Adjusted* 
Men OR 95% C.I. P OR 95% C.I. P 
Age per 1 year increase 0.994 0.982-1.006 0.32 0.990 0.976-1.004 0.15 
Body mass index per 1 kg/m
2
 increase 1.050 0.999-1.103 0.054 0.982 0.927-1.040 0.53 
Smoking habits positive vs negative 0.915 0.705-1.187 0.50 1.016 0.759-1.359 0.92 
Drinking habits positive vs negative 0.776 0.597-1.008 0.058 0.765 0.571-1.025 0.072 
Baseline eGFR per 1 mL/min/1.73m
2
 increase 1.006 0.996-1.015 0.23 1.010 0.999-1.022 0.073 
Baseline LDL cholesterol per 1 mg/dL increase 1.077 1.065-1.088 <0.001 1.081 1.069-1.093 <0.001 
Baseline serum uric acid per 1 mg/dL increase 1.050 0.940-1.174 0.39 1.159 1.009-1.331 0.037 
Serum uric acid change per 1 mg/dL increase 1.343 1.135-1.591 <0.001 1.709 1.401-2.084 <0.001 
 
Women OR 95% C.I. P OR 95% C.I. P 
Age per 1 year increase 1.045 1.035-1.055 <0.001 1.004 0.993-1.016 0.46 
Body mass index per 1 kg/m
2
 increase 1.159 1.120-1.199 <0.001 1.068 1.028-1.110 <0.001 
Smoking habits positive vs negative 0.827 0.644-1.062 0.14 0.816 0.612-1.090 0.17 
Drinking habits positive vs negative 0.662 0.536-0.818 <0.001 0.939 0.736-1.197 0.61 
Baseline eGFR per 1 mL/min/1.73m
2
 increase 0.996 0.990-1.002 0.24 1.009 1.002-1.017 0.016 
Baseline LDL cholesterol per 1 mg/dL increase 1.088 1.079-1.096 <0.001 1.087 1.079-1.096 <0.001 
Baseline serum uric acid per 1 mg/dL increase 1.216 1.095-1.350 <0.001 1.215 1.061-1.390 0.005 
Serum uric acid change per 1 mg/dL increase 1.630 1.409-1.886 <0.001 2.031 1.700-2.426 <0.001 
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b)Low HDL cholesterol 
 
 Crude Adjusted† 
Men OR 95% C.I. p OR 95% C.I. P 
Age per 1 year increase 1.008 0.981-1.036 0.58 1.017 0.986-1.050 0.28 
Body mass index per 1 kg/m
2
 increase 1.149 1.027-1.285 0.015 0.949 0.829-1.087 0.45 
Smoking habits positive vs negative 0.822 0.442-1.527 0.53 0.783 0.398-1.543 0.48 
Drinking habits positive vs negative 0.654 0.352-1.216 0.18 1.162 0.587-2.300 0.67 
Baseline eGFR per 1 mL/min/1.73m
2
 increase 0.987 0.963-1.011 0.28 0.997 0.969-1.026 0.86 
Baseline HDL cholesterol per 1 mg/dL increase 0.760 0.704-0.821 <0.001 0.761 0.704-0.823 <0.001 
Baseline serum uric acid per 1 mg/dL increase 1.447 1.130-1.930 0.004 1.309 0.937-1.827 0.11 
Serum uric acid change per 1 mg/dL increase 0.864 0.584-1.279 0.465 0.968 0.631-1.486 0.88 
 
Women OR 95% C.I. p OR 95% C.I. P 
Age per 1 year increase 0.987 0.927-1.051 0.69 0.986 0.917-1.060 0.70 
Body mass index per 1 kg/m
2
 increase 1.303 1.125-1.508 <0.001 1.143 0.956-1.367 0.14 
Smoking habits positive vs negative 1.560 0.421-5.777 0.51 1.141 0.288-4.515 0.85 
Drinking habits positive vs negative 0.204 0.026-1.5860.13 0.357 0.042-3.016 0.34 
Baseline eGFR per 1 mL/min/1.73m
2
 increase 0.999 0.962-1.038 0.97 0.988 0.947-1.031 0.59 
Baseline HDL cholesterol per 1 mg/dL increase 0.803 0.738-0.872 <0.001 0.814 0.748-0.885 <0.001 
Baseline serum uric acid per 1 mg/dL increase 1.055 0.547-2.034 0.87 0.733 0.342-1.570 0.42 
Serum uric acid change per 1 mg/dL increase 0.807 0.320-2.037 0.65 0.719 0.275-1.878 0.50 
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c)Hypertriglyceridemia 
 
 Crude Adjusted‡ 
Men OR 95% C.I. p OR 95% C.I. P 
Age per 1 year increase 0.980 0.967-0.993 0.003 0.979 0.963-0.995 0.010 
Body mass index per 1 kg/m
2
 increase 1.127 1.069-1.188 <0.001 1.018 0.959-1.081 0.56 
Smoking habits positive vs negative 1.671 1.237-2.259 <0.001 1.465 1.047-2.051 0.026 
Drinking habits positive vs negative 1.308 0.967-1.768 0.082 0.953 0.681-1.332 0.78 
Baseline eGFR per 1 mL/min/1.73m
2
 increase 1.005 0.995-1.015 0.32 1.006 0.994-1.018 0.37 
Baseline triglyceride per 1 mg/dL increase 1.038 1.032-1.044 <0.001 1.036 1.031-1.042 <0.001 
Baseline serum uric acid per 1 mg/dL increase 1.438 1.270-1.628 <0.001 1.370 1.179-1.591 <0.001 
Serum uric acid change per 1 mg/dL increase 1.264 1.053-1.518 0.012 1.517 1.244-1.850 <0.001 
 
Women OR 95% C.I. P OR 95% C.I. P 
Age per 1 year increase 1.004 0.982-1.027 0.74 0.959 0.934-0.985 0.002 
Body mass index per 1 kg/m
2
 increase 1.187 1.108-1.271 <0.001 1.063 0.986-1.146 0.11 
Smoking habits positive vs negative 1.947 1.214-3.123 0.006 1.224 0.732-2.044 0.44 
Drinking habits positive vs negative 1.642 1.065-2.533 0.025 1.463 0.913-2.342 0.11 
Baseline eGFR per 1 mL/min/1.73m
2
 increase 0.979 0.964-0.995 0.010 0.981 0.964-0.999 0.038 
Baseline triglyceride per 1 mg/dL increase 1.039 1.032-1.046 <0.001 1.038 1.030-1.046 <0.001 
Baseline serum uric acid per 1 mg/dL increase 1.894 1.506-2.382 <0.001 1.942 1.462-2.578 <0.001 
Serum uric acid change per 1 mg/dL increase 1.748 1.255-2.433 <0.001 2.219 1.578-3.121 <0.001 
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eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; HDL, high-density lipoprotein; OR, odds ratio; C.I., 
confidence interval; p, probability 
*Data adjusted for age, body mass index, smoking and drinking habits, eGFR, baseline serum uric acid, serum uric acid change, and 
baseline LDL cholesterol 
†Data adjusted for age, body mass index, smoking and drinking habits, eGFR, baseline serum uric acid, serum uric acid change, and 
baseline HDL cholesterol 
‡Data adjusted for age, body mass index, smoking and drinking habits, eGFR, baseline serum uric acid, serum uric acid change, and 
baseline triglyceride 
 
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Figure legends 
Figure 1. Flow diagram of study enrollment. 
 
Figure 2. The cumulative incidences for developing dyslipidemia over 5 years in each 
serum uric acid level by sex. 
Men: The numbers of subjects were 11 in ≤ 3.0 mg/dL, 104 in 3.0 to 4.0 mg/dL, 306 in 4.0 
to 5.0 mg/dL, 753 in 5.0 to 6.0 mg/dL, 668 in 6.0 to 7.0 mg/dL, 309 in 7.0 to 8.0 mg/dL, 92 
in more than 8.0 mg/dL of serum uric acid levels. The mean cumulative incidence of 
dyslipidemia was 21.0%. Serum uric acid levels was positively correlated with cumulative 
incidences of dyslipidemia over 5 years by Pearson’s correlation coefficient (R=0.96, 
p=0.001). 
Women: The numbers of subjects were 11 in ≤ 2.0 mg/dL, 270 in 2.0 to 3.0 mg/dL, 1,400 
in 3.0 to 4.0 mg/dL, 1,827 in 4.0 to 5.0 mg/dL, 597 in 5.0 to 6.0 mg/dL, 114 in 6.0 to 7.0 
mg/dL, 14 in more than 7.0 mg/dL of serum uric acid levels. The mean cumulative 
incidence of dyslipidemia was 15.0%. Serum uric acid levels was positively correlated with 
cumulative incidences of dyslipidemia over 5 years by Pearson’s correlation coefficient 
(R=0.94, p<0.001). 
 
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Highlights 
 
 This study clarified the relationship between serum uric acid (SUA) and lipid. 
 High baseline SUA is an independent risk for developing high LDL cholesterol. 
 Increased SUA over 5 years is also a risk for developing high LDL cholesterol. 
 Increased SUA is a risk for hypertriglyceridemia, but not for low HDL cholesterol. 
 It shows a potential mechanism in which high SUA may cause cardiovascular disease. 
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Figure 2