Acta Cardiologica

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Dose–response association between serum uric

acid levels and incident hypertension: a systematic
review and meta-analysis of 17 prospective cohort
studies of 32 thousand participants

Leilei Liu, Xiao Zhang, Ranran Qie, Minghui Han, Quanman Li, Linyuan
Zhang, Shaohui Zhan, Juntao Zhang, Cailiang Zhang & Feng Hong

To cite this article: Leilei Liu, Xiao Zhang, Ranran Qie, Minghui Han, Quanman Li, Linyuan
Zhang, Shaohui Zhan, Juntao Zhang, Cailiang Zhang & Feng Hong (2020): Dose–response
association between serum uric acid levels and incident hypertension: a systematic review and
meta-analysis of 17 prospective cohort studies of 32 thousand participants, Acta Cardiologica, DOI:
10.1080/00015385.2020.1779476

To link to this article: https://doi.org/10.1080/00015385.2020.1779476

Published online: 15 Jun 2020.

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ACTA CARDIOLOGICA
https://doi.org/10.1080/00015385.2020.1779476

ORIGINAL SCIENTIFIC PAPER

Dose–response association between serum uric acid levels and incident

hypertension: a systematic review and meta-analysis of 17 prospective
cohort studies of 32 thousand participants
Leilei Liua, Xiao Zhanga, Ranran Qieb, Minghui Hanb, Quanman Lib, Linyuan Zhanga, Shaohui Zhana,
Juntao Zhanga, Cailiang Zhanga and Feng Honga
a
School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education,
Guizhou Medical University, Guiyang, China; bCollege of Public Health, Zhengzhou University, Zhengzhou, China

ABSTRACT ARTICLE HISTORY

Background: Various magnitudes of the risk of incident hypertension (IHTN) have been Received 30 April 2020
reported to be associated with increased serum uric acid (SUA) levels in observational studies, Revised 29 May 2020
however, whether a dose–response relation exists is unclear. We aimed to quantitatively evalu- Accepted 2 June 2020
ate the SUA–IHTN association.
KEYWORDS
Methods: We searched the PubMed and Embase databases for relevant articles published prior Dose–response; serum uric
to 21 October 2019. Random-effects models were used to estimate the summary relative risks acid; hypertension;
(RRs) and 95% confidence intervals (CIs) of the IHTN risk in relation to SUA levels. We used prospective studies; risk
restricted cubic splines to model the dose–response association between SUA levels and IHTN.
Results: A total of 17 articles (17 prospective cohort studies) including 321,716 adults and
65,890 IHTN cases were identified. The pooled RR was 1.10 (95% CI 1.07–1.13; I2¼90.7%; n ¼ 17)
per 1 mg/dL change in the SUA level. In addition, we found evidence of a linear and positive
dose–response association between SUA levels and IHTN (Pnon-linearity ¼ 0.069). The results of
the subgroup and sensitivity analyses were consistent with those of the primary analysis.
Conclusion: These data suggested that people with higher SUA levels had a higher IHTN risk.
SUA levels need to be controlled to reduce or eliminate the risk of IHTN associated with SUA
levels. Clinical trial studies or diagnostic studies are needed to determine the optimal cut-off
point for SUA.

Introduction risk-reduction view is needed, and primary HTN cases

Hypertension (HTN) is one of the most common med-
ical conditions, and it affects public health worldwide.
The 2017 Global Burden of Disease Study suggested
that HTN leads to several adverse outcomes; for
example, 911.2 thousand chronic kidney disease cases
occur globally [1]. Additionally, HTN has been consid-
ered the leading cause of death worldwide over the
years [2]. The effects of HTN are daunting, given that
the global prevalence of HTN increased by approxi-
mately 10% between 2000 and 2025 [3]. In view of
the increasing prevalence and severe disease burden
of HTN, an HTN Commission was launched by The
Lancet to start a campaign to implement priority
actions to reduce the morbidity and mortality associ-
ated with HTN globally [4]. A better understanding of
the risk factors related to HTN from a whole-person
should be screened to lower the disease burden
caused by HTN.
The concept that serum uric acid (SUA) may be
associated with multiple health outcomes, such as
HTN, is not a new concept; increasingly more general
population-based articles on this topic are being pub-
lished [5–8], and they have demonstrated that an ele-
vated SUA level is a potential independent risk factor
for HTN in the general population [9–11]. Notably,
these findings have led to a renewed interest in recent
years regarding whether a dose–response SUA–HTN
association exists; however, no specific assessment has
been conducted to date. The potential adverse rela-
tion of SUA levels with HTN risk should be taken into
consideration, and the prevention, management, and
treatment of SUA–associated HTN should be
addressed. Assessments of the credibility of the results

CONTACT Feng Hong fhong@gmc.edu.cn School of Public Health, the Key Laboratory of Environmental Pollution Monitoring and Disease Control,
Ministry of Education, Guizhou Medical University, Guiyang 550025, China
Supplemental data for this article is available online at https://doi.org/10.1080/00015385.2020.1779476.
ß 2020 Belgian Society of Cardiology
2 L. LIU ET AL.
observed in previous studies may have implications
both for clinical practice and public health regarding
the potential importance of SUA.
Here, we attempted to summarise and present the
SUA–associated incident HTN (IHTN) risk and evaluate
the existing evidence to verify the underlying dose–r-
esponse SUA–IHTN association in adult populations
using all available data from a total of 17 prospective
cohort studies.
Methods
Data sources and searches
We searched the PubMed and Embase electronic data-
bases for all articles on prospective cohort studies that
investigated the SUA–IHTN association and were pub-
lished prior to 21 October 2019. The detailed search
strategy is given in Supplementary Table 1. The refer-
ence lists of all included studies and previous system-
atic reviews and meta-analyses were manually
searched for additional relevant studies.
Study selection
Prospective cohort studies were included if they (a)
evaluated the SUA–IHTN relation in adults (18 years
old at baseline); (b) reported odds ratios (ORs), hazard
ratios (HRs), relative risks (RRs) with 95% confidence
intervals (CIs), or sufficient data for deriving these val-
ues; and (c) reported sufficient on risk estimates for at
least 3 categories or continuous SUA measurements,
SUA levels at baseline, and the number of people and
cases corresponding to each level or calculated them
by sufficient data so that we could perform dose–res-
ponse analysis. In addition, the exclusion criteria were
(a) studies including people with HTN at baseline; (b)
studies reporting SUA as a dichotomous variable; and
(c) cross–sectional studies, case–control studies, non-
prospective cohort studies, reviews, meta-analyses,
studies with unusable data, and conference abstracts.
Additionally, for published duplicate articles based on
the same cohort, we included the data with the larger
number of incident outcomes or sample sizes.
Data extraction and quality assessment
Two authors (Leilei Liu and Xiao Zhang) extracted data
on the first author, publication year, region, duration
of follow-up, sample size (number of people and
cases), participants sex, participants age, reported lev-
els of SUA exposure, number of participants and cases
corresponding to the levels, RRs/HRs/ORs with 95%
CIs, and the model was adjusted for potential con-
founders in the multivariable analysis. Leilei Liu and
Xiao Zhang extracted the relevant data and reviewed
the data, respectively, and all discrepancies were
resolved by discussion. Leilei Liu and Xiao Zhang per-
formed quality assessments for the included studies
using the Newcastle–Ottawa Scale (NOS) [12].
Data synthesis and analysis
We assumed that the HRs or ORs were approximately
the same as the RRs [13] for articles that reported ORs
or HRs for IHTN, and we also extracted the multivari-
ate-adjusted RRs with the 95% CIs. Summary RRs and
95% CIs were estimated by using a fixed-effects model
when heterogeneity (I2)<50%; otherwise, a random-
effects model was used. Data that was reported separ-
ately in the results by participants sex were pooled
with the fixed-effects model before inclusion in the
meta-analysis, and the original data were still used for
subgroup analysis stratified by sex.
Heterogeneity was assessed by the Cochran Q and
I2 statistics, and p < 0.10 was considered statistically
significant for the Q statistic [14]. We performed sub-
group analyses stratified by sex, region, follow-up
year, sample size, number of cases, and HTN criteria
(140/90 mmHg or not), and the covariates (age,
smoking, alcohol drinking, physical activity, body mass
index, and family history of HTN) were adjusted for in
the analysis. A sensitivity analysis was performed by
excluding one study at a time, and whether the results
were strongly influenced by a single study was eval-
uated. Additionally, we used Egger’s [15] test to evalu-
ate potential publication bias. The trim-and-fill method
was used when we found evidence of publica-
tion bias.
All analyses were performed with Stata 12.1 (Stata
Corp, College Station, TX, USA), and a two-sided
p < 0.05 was considered statistically significant.
Results
Descriptive study characteristics
The literature search identified 4,599 potentially rele-
vant records, and 17 articles [6,11,16–30] (17 prospect-
ive cohort studies) met the prespecified inclusion
criteria (Supplementary Figure 1). Overall, the meta-
analysis included 321,716 participants and 65,890 HTN
incident cases over a median follow-up of 7 years, and
all studies involved adult populations (18 years old
at baseline). Supplementary Table 2 shows the main
characteristics of each study. In summary, 10 studies

Figure 1. Forest plot of study–specific relative risk statistics for incident hypertension per 1 mg/dL changes in the serum uric acid
concentration. CI: confidence interval; RR: relative risk.
included both sexes [11,16–19,22,26,28,29], 12 per-
formed stratified analyses by sex [6,16,19–29], and 1
analysed only men [30]. Of the 17 studies, 12 were
conducted in Asia [6,16,18,21–28,30] (6 in China
[6,18,21–23,28], 3 in Japan [26,27,30], 2 in Korea
[16,24], and 1 in Israel [25]), 4 were conducted in the
United States [11,19,20,29], and 1 was conducted in
Europe [17] (Portugal). The average NOS score regard-
ing study quality was 8 (range 7–9).
Dose–response analysis for the SUA-IHTN
association
In total, 17 studies were included in the dose–res-
ponse analysis. A 1 mg/dL increase in the SUA concen-
tration was associated with a 1.10-fold increase in the
risk of IHTN (RR 1.10; 95% CI 1.07–1.13; I2 ¼ 90.7%;
Pheterogeneity < 0.001) (Figure 1). We detected statistic-
ally significant publication bias by Egger’s test
(p ¼ 0.005). The main result was attenuated but
remained significant (RR 1.07, 95% CI 1.04–1.10) when
the trim-and-fill method was used. After excluding the
studies reporting only continuous risk estimates, we
ACTA CARDIOLOGICA 3
found a linear positive SUA–IHTN association in 8
studies (Pnon-linearity ¼ 0.069, Figure 2).
Subgroup and sensitivity analyses
To explore the sources of heterogeneity, we per-
formed subgroup analyses (Table 1). The effect of SUA
exposure was not protective in all subgroup analyses
performed by sex, region, follow-up year, sample size,
the number of cases, HTN criteria, and confounding
factors (Table 1). We observed that the level of hetero-
geneity was lower among studies with 500 cases
and Americans, without adjustments for body mass
index. Additionally, after we removed one study at a
time, we found that the sizes or directions of the
pooled estimates were similar for most of the sensitiv-
ity analysis results.
Discussion
To the best of our knowledge, this is the first largest
and most comprehensive systematic review and meta-
analysis examining the dose–response SUA–IHTN asso-
ciation. This meta-analysis of 17 prospective cohort
4 L. LIU ET AL.

from this meta-analysis suggested that the risk of

IHTN increased by 10% per 1 mg/dL increase in the
SUA concentration. Moreover, the present analysis
indicated a linear dose–response SUA–IHTN relation.
Most importantly, none of the dose–response asso-
ciations were explored in previous relevant meta-anal-
yses [5–10]. Additionally, the previous meta-analyses
assessed the hyperuricemia–IHTN relation [9,10], and
SUA was not analysed as a continuous variable.
Moreover, the previous meta-analyses included people
of all ages, such as children [7], or different study
designs [5,9]; however, subgroup analyses for factors
Figure 2. Linear dose–response relation between serum uric [5–7] such as sex, region, or HTN criteria were not per-
acid levels and risk of incident hypertension that was assessed
formed to evaluate the potential relationship among
by using a restricted cubic splines model. CI: confidence inter-
val; RR: relative risk; SUA: serum uric acid. different groups and the level of heterogeneity. The
professional populations were also not exclude [10].
Table 1. Serum uric acid subgroup analysis of the risk of inci-
dent hypertension. The study types and participants in the present meta-
Dose–response analysis (per 1 mg/dL) analysis were limited to prospective cohort studies
Characteristics n RR (95% CI) I2 (%) Pheterogeneity and adult populations, with strict inclusion and exclu-
All studies 17 1.10 (1.07–1.13) 90.7 <0.001 sion criteria and a mean follow-up of more than
Sex 7 years, making the results highly credible. Some sub-
Men/Women 15 1.11 (1.07–1.14) 89.0 <0.001
Men 12 1.08 (1.06–1.11) 82.5 <0.001 group analyses were conducted, and we found a lin-
Women 11 1.11 (1.07–1.15) 87.0 <0.001 ear dose–response SUA–IHTN association.
Region
Asia 12 1.09 (1.06–1.12) 92.5 <0.001 Several possible biological mechanisms can explain
America 4 1.12 (1.09–1.16) 42.0 0.159 the SUA–HTN relation. Mutation occurs in the uricase
Europe 1 1.34 (0.80–2.27) – –
Follow–up year gene in humans [31], and it can not only mediate
<10 years 12 1.07 (1.05–1.10) 77.8 <0.001 microvascular changes in the SUA level but also
10 years 5 1.14 (1.06–1.21) 91.4 <0.001
Sample size induce reversible sodium-resistant HTN [32,33].
<10,000 13 1.10 (1.07–1.13) 72.2 <0.001 Additionally, increases in juxtaglomerular renin pro-
10,000 4 1.10 (1.04–1.17) 97.4 <0.001
Number of cases duction and reductions in neuronal NO synthase in
<500 4 1.15 (1.04–1.27) 92.5 <0.001 the macula densa may contribute to HTN develop-
500 13 1.05 (1.04–1.06) 24.3 0.265
Hypertension criteria (140/90 mmHg) ment [34]. Additional mechanisms that contribute to
Yes 14 1.09 (1.06–1.12) 91.4 <0.001 changes in the SUA level may be associated with
No 3 1.20 (1.13–1.27) 0.0 0.889
Adjustments arteriolar thickening [35], the proliferation of vascular
Age smooth muscle cells [34], and various degrees of renal
Yes 16 1.11 (1.07–1.14) 91.2 <0.001
No 1 1.04 (1.01–1.07) – – dysfunction (such as glomerular hypertrophy and
Smoking interstitial fibrosis) to promote HTN [11,36,37]. The
Yes 12 1.10 (1.06–1.14) 92.6 <0.001
No 5 1.11 (1.05–1.18) 78.4 0.001 potential mechanistic role of SUA in the risk of HTN is
Alcohol drinking complex and remains unclear and needs to be
Yes 11 1.09 (1.06–1.12) 83.8 <0.001
No 6 1.11 (1.05–1.18) 93.0 <0.001 studied further.
Physical activity
Yes 7 1.12 (1.06–1.19) 88.8 <0.001
No 10 1.09 (1.05–1.14) 91.9 <0.001
Body mass index
Strengths and limitations
Yes 13 1.10 (1.07–1.14) 92.7 <0.001
No 4 1.09 (1.02–1.18) 54.3 0.087 A prominent strength of our meta-analysis is that a
Family history of hypertension dose–response analysis was performed to verify there
Yes 2 1.06 (1.00–1.13) 86.3 0.007
No 15 1.11 (1.07–1.15) 91.2 <0.001 is a linear dose–response relation between SUA levels
CI: confidence interval; RR: relative risk. –: not applicable. and IHTN. Additionally, the prospective design poten-
tially minimised the selection bias and recall bias and
studies with 65,890 incident cases among 321,716 par- provided sufficient statistical power. Furthermore, the
ticipants provides a quantitative comprehensive large sample size contributed to a highly accurate and
assessment of the SUA–IHTN association. The results precise pooled risk estimate. Finally, the robustness of

the results of the subgroup and sensitivity analyses
was similar to that of the principal findings.
There are some weaknesses of the meta-analysis
that are worth mentioning. First, we may not have
principally suggested causality in the summary of the
SUA–IHTN association because all studies included in
this meta-analysis had an observational design.
Second, the current results may not be generalised
because of the limitations of the original studies (the
relevant analysis was not carried out in some specific
populations, such as the European population). Third,
we could not analyse the association between SUA
and the IHTN subtype given the small amount of data.
Fourth, because the data was limited, the subgroup
analysis of the HTN criteria was classified based on
only the dichotomy data. Finally, residual confounding
bias may be inevitable owing to the unmeasured and
insufficiently measured variables.
Conclusions
Our present findings provide quantitative data sug-
gesting that elevated SUA levels may increase the risk
of IHTN. We determined that elevated SUA levels may
have adverse effects, such as IHTN. However, clinical
trial studies or diagnostic studies are also needed to
determine the optimal cut-off point. We expect that
this linear association exists for the IHTN subtype
when there are enough data available. Additional
studies are needed to determine the relation between
SUA and other types of IHTN and the mechanisms
that cause the SUA–IHTN association. Other popula-
tion-specific studies are also needed. It is beneficial for
the development of future research to address the
limitations and caveats in the existing studies.
Acknowledgements
As this meta-analysis is performed based on the published
studies, no ethical approval and patient safety considera-
tions are required. The investigators are grateful for the
dedicated participants and all research staff who participated
in the study.
Disclosure statement
No potential conflict of interest was reported
the author(s).
Funding
This study was supported by the National Key R&D
Programme of China [NO.2017YFC0907301].
ACTA CARDIOLOGICA 5
ORCID
Feng Hong http://orcid.org/0000-0002-6329-5331
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