Received: 1 July 2023 | Revised: 31 July 2023 | Accepted: 4 August 2023

DOI: 10.1002/edm2.446

RESEARCH ARTICLE

Serum uric acid to high-­density lipoprotein ratio as a novel

indicator of inflammation is correlated with the presence and
severity of metabolic syndrome: A large-­scale study

Rana Kolahi Ahari1 | Amin Mansoori1,2 | Toktam Sahranavard1 | Monireh Sadat Miri3 |
Sara Feizi3 | Habibollah Esmaily2 | Majid Ghayour-­Mobarhan1

1
International UNESCO Center for
Health-­Related Basic Sciences and Human Abstract
Nutrition, Mashhad University of Medical
Introduction: We investigated the association of serum uric acid to high-­density li-
Sciences, Mashhad, Iran
2
Department of Biostatistics, School of
poprotein ratio (UHR) with the presence and severity of metabolic syndrome (MetS)
Health, Mashhad University of Medical among MASHAD cohort participants.
Sciences, Mashhad, Iran
3
Methods: In this cross-­sectional study, according to International Diabetes Federation
Department of Biology, Faculty of
Sciences, Mashhad Branch, Islamic Azad criteria, the cohort participants were divided into MetS (+) and MetS (−) groups.
University, Mashhad, Iran MetS (+) were classified into Group 1 (those with 3 MetS criteria), Group 2 (those with
Correspondence 4 MetS criteria) and Group 3 (those with 5 MetS criteria). UHR was compared among
Majid Ghayour-­Mobarhan, Department the groups.
of Nutrition, Faculty of Medicine,
International UNESCO Center for Results: Data related to 9637 subjects including 3824 MetS (+) and 5813 MetS (−)
Health-­Related Basic Sciences and Human were analysed. The mean UHR was significantly higher (p < .001) in the MetS (+) group
Nutrition, Mashhad University of Medical
Sciences, Mashhad 99199-­91766, Iran. compared with the MetS (−) group. UHR increased as the MetS severity increased
Email: [email protected] (p < .001). ROC analysis revealed that UHR greater than 9.5% has 89.07% sensitivity
Habibollah Esmaily, Department of and 77.03% specificity in differentiating MetS (−) from MetS (+) subjects.
Biostatistics, School of Health, Social
Determinants of Health Research Center,
Conclusion: Among MASHAD cohort study participants, a significant association be-
Mashhad University of Medical Sciences, tween UHR and MetS was found. Furthermore, there is an increase in UHR as the
Mashhad, Iran.
Email: [email protected]
severity of MetS increases. Registration number of MASHAD cohort study: 85134.

KEYWORDS
high-­density lipoprotein, metabolic syndrome, UHR, uric acid

1 | I NTRO D U C TI O N that obesity-­induced inflammatory processes may lead to a state of

chronic low-­grade inflammation, which plays an important role in the
Metabolic syndrome (MetS) is defined as a cluster of symptoms such development of insulin resistance that triggers the associated MetS
as hyperglycaemia/insulin resistance, obesity, hypertension (HTN) comorbidities such as atherosclerosis, HTN, dyslipidaemia, hyper-
and dyslipidaemia and it is directly linked to a higher risk of devel- glycaemia and prothrombotic state. 2,3
oping atherosclerotic cardiovascular disease (CVD), diabetes mel- Moreover, uric acid (UA) as the end product of endogenous and
litus (DM) and all-­cause mortality.1 The prevalence of MetS began exogenous purine metabolism by xanthine oxidase, causes insulin
to increase globally due to obesity epidemics. It has been reported resistance and atherosclerosis by platelet dysfunction, reducing

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.

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2 of 9 KOLAHI AHARI et al.

the production of nitric oxide, endothelial dysfunction and oxida- 1. Raised concentration of triglycerides (TGs): ≥150 mg/dL
tive metabolism. Studies showed that increased insulin secretion (1.7 mmol/L) or receives specific treatment for this lipid
increases serum UA levels due to a decline in renal function and abnormality;
serum UA concentration is independently correlated with MetS 2. Reduced concentration of HDL cholesterol: <40 mg/dL
risk factors, HTN, kidney disease and cardiovascular events.4,5 (1.03 mmol/L) in men and <50 mg/dL (1.29 mmol/L) in women or
UA can also induce inflammatory and oxidative changes in adipo- receives specific treatment for this lipid abnormality;
cytes.6,7 On the contrary, high-­density lipoprotein (HDL) known as 3. Raised fasting plasma glucose concentration: ≥100 mg/dL
‘good’ cholesterol is a cardioprotective biomarker, which removes (5.6 mmol/L) or previously diagnosed with DMII;
excess cholesterol from peripheral tissues and transports it to the 4. Raised blood pressure: systolic blood pressure (SBP) ≥130 mmHg
liver; for HDL, a spectrum of antiapoptotic, antithrombotic, anti-­ or diastolic blood pressure (DBP) ≥85 mmHg or receives treat-
inflammatory and antioxidative activities have been shown. 8 A low ment for previously diagnosed HTN.
concentration of HDL is identified as an independent predictor of
CVD risk. On the contrary, it was discovered that depending on the Then, subjects classified as MetS (+) group were divided into
presence or absence of inflammation, HDL may act both as an anti-­ three subgroups based on the number of MetS criteria they had as
inflammatory or pro-­inflammatory factor for multiple metabolic dis- follows: group 1 (patients with three MetS criteria), group 2 (patients
orders. Indeed, in addition to the quantity of HDL, the quality of with four MetS criteria) and group 3 (patients with five MetS cri-
HDL particles appears to be crucial and should be considered.9-­12 teria). Rest of the population was selected as MetS (−) group. The
Investigations suggest that combination of HDL and serum UA may flowchart of current study design outlined in Figure 1.
be a better predictor of CVD morbidity and mortality than either
alone.11 Recently, serum UA to HDL ratio (UHR) has been reported
as a novel inflammatory and metabolic marker, which increases in 2.2 | Ethical consideration
inflammatory conditions such as steatohepatitis and Hashimoto's
thyroiditis.13 The predictive value of UHR has also been validated in All participants included in the study were informed about the study,
DM and MetS.14,15 However, whether UHR is associated with MetS and signed a written informed consent form before inclusion. The
severity remains unclear. study was approved by the Ethic Committee of Mashhad University
Since the prevalence of hyperuricaemia and MetS has been in- of Medical Sciences.
creasing not only in advanced countries but also in developing
countries,16 the early diagnosis is a crucial issue. Also, due to both
anti-­inflammatory and pro-­inflammatory properties of total HDL 2.3 | Anthropometric measurements
and since few studies assessed the relationship between UHR as a
novel and easy-­to-­assess metabolic marker and MetS in a large-­scale Anthropometric measurements including height, weight and waist
population so far, the present study intended to compare the UHR circumference (WC) were obtained. Height was measured by a
between MetS patients and non-­MetS ones enrolled in MASHAD standard wall height meter. Weight was measured by an analogue
17
cohort study and examine correlations between UHR and of MetS scale, which was kept on a firm horizontal surface. WC was meas-
severity. ured with a non-­stretchable fibre measuring tape. The body mass
index (BMI) was calculated as the weight (kg) divided by the square
of the height (m).
2 | M E TH O D

2.1 | Study design and population 2.4 | Blood pressure

The target population was recruited from the Mashhad Stroke and Participants were requested to relax for at least 15 min. Then, blood
Heart Atherosclerotic Disorder (MASHAD) study, a 10-­year prospec- pressure of the right arm was measured and repeated after 10 and
tive cohort from Mashhad city, northeast of Iran. The methodology 20 min (a total of three times). If taking the blood pressure from the
and sampling details have been published elsewhere.17 In brief, 9704 right arm was not successful, the left arm was considered. The mean
individuals aged 35–­65 years were recruited using stratified cluster of the three measurements was recorded as the participant's final
random sampling technique. The socio-­demographic, hematologic, an- blood pressure.
thropometric and biochemical data were collected. Those whose bio-
chemical data was not available were excluded from the present study.
In our study, MetS is defined based on the International Diabe- 2.5 | Biochemical parameters
tes Federation (IDF).18 According to the IDF definition, someone has
MetS if she or he has central obesity (≥94 cm for men and ≥80 cm for In our laboratory unit, a 20-­m L blood sample was taken from each
women) plus two or more of the following four factors: participant. Blood samples were taken between 8 and 10 a.m. by
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KOLAHI AHARI et al. 3 of 9

F I G U R E 1 Flowchart of the present

MASHAD Study
study participants and grouping.
participants
(n=9704)
Exclusion criteria:
Those whose biochemical data was not
available

A total of 9637 subjects

were included in the study

Metabolic syndrome identified according

to International Diabetes Federation (IDF)

MetS (+) MetS (-)

n=3824 n= 5813

Group 1 Group 2 Group 3

(Criteria score=3) (Criteria score=4) (Criteria score=5)

venipuncture of an antecubital vein after 14 h of overnight fasting. Let Yi denotes the response variable and takes the values of 0 or
According to standard protocol, samples were collected in vac- 1 depending on whether response occurs or not. Also, X be vectors
uum tubes (20 mL) from subjects in a sitting position and imme- of covariates associated with response variable, 𝜷 is the correspond-
diately centrifuged at room temperature to separate the plasma ing vectors of regression coefficients. So, the association between
and serum into six aliquots (0.5 mL) and then sent to the MA- the covariates and binary response variable can be investigated as
SHAD study biobank. BT3000 biochemical analyser was used for follows:
determination of biochemical parameters levels including: fasting { ( )} ( )
logit E Yi = logit { Pr Yi = 1|X, 𝜷 = 𝜷 T X
blood glucose (FBG), UA, high-­s ensitivity C-­reactive protein (hs-­
CRP), Low-­d ensity lipoprotein (LDL), total cholesterol (TC), TGs
and HDL. All devices were daily checked by a laboratory techni- 3 | R E S U LT S
cian. UHR was calculated as the ratio of serum UA (mg/dL) to HDL
(mg/dL). A total of 9704 subjects were enrolled to the MASHAD cohort
study. After applying exclusion criteria, data related to 9637 eligible
patients were analysed (3824 with MetS and 5813 without MetS)
2.6 | Statistical analysis and model building (Figure 1). Comparisons of the basic characteristics of the MetS (+)
and MetS (−) groups are shown in Table 1. Mean ages of MetS (+) and
To describe the quantitative and qualitative variables, mean ± SD MetS (−) patients were 46.90 ± 8.18 and 50.01 ± 7.98 years, respec-
and frequency (%) are reported, respectively. The Chi-­squared test tively, indicated a significant difference (p < .001). In MetS (+) group,
and Fisher's exact test were applied to measure the association be- 1184 (30.96%) were male and 2640 (69.04%) were female and in the
tween categorical variables. Also, the mean of quantitative variables MetS (−) group, 2663 (45.81%) were male and 3150 (54.19%) were
between the MetS (+) and MetS (−) groups were compared by in- female. There was a significant difference between the two groups
dependent t test. In addition, logistic regression (LR) algorithm was in terms of gender (p < .001). There was significant difference be-
used to analyse data. In fact, we applied the algorithm to deduce tween the two groups in terms of BMI, WC, SBP, DBP, hs-­CRP, TC,
the association between MetS and related factors. All analysis was LDL, TGs and FBG as well (p < .001). On the contrary, smoking sta-
performed using SPSS version 22 (IBM Corp.). tus was not statistically significantly different between the groups
(p = .53). The mean HDL level in the MetS (+) group was significantly
lower than the MetS (−) group (39.68 ± 8.32 vs. 44.92 ± 10.37 mg/
2.7 | Logistic regression (LR) modelling dL, respectively, p < .001). The mean UA level in the MetS (+) and
MetS (−) group was 4.89 ± 1.41 and 4.49 ± 1.36 mg/dL, respectively
LR is a popular model to evaluate the relationship between various (p < .001). Accordingly, MetS (+) group had a significantly higher
predictor variables (either categorical or continuous) and binary out- UHR compared to the MetS (−) group (0.13 ± 0.05 vs. 0.11 ± 0.04 mg/
comes in medicine, public health, etc.19-­23 dL, respectively, p < .001).
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4 of 9 KOLAHI AHARI et al.

TA B L E 1 Baseline and clinical

MetS (−) (n = 5813, MetS (+) (n = 3824,
characteristics of study population
Characteristics 60.32%) 39.68%) p-­Value*
from Mashhad Stroke and Heart
Sex Atherosclerotic Disorder (MASHAD)
Female 3150 (54.19%) 2640 (69.04%) <.001 study.

Male 2663 (45.81%) 1184 (30.96%)

Smoking status
Smoker 1270 (21.84%) 798 (20.86%) .53
Non-­smoker 3990 (68.63%) 2628 (68.72%)
Ex-­smoker 553 (9.51%) 398 (10.40%)
Diabetes
Diabetic 392 (6.81%) 965 (25.41%) <.001
Non-­diabetic 5361 (93.19%) 2832 (74.58%)
HTN
HTN+ 997 (17.18%) 2015 (52.92%) <.001
HTN− 4807 (82.82%) 1793 (47.08%)
Age (year) 46.90 ± 8.18 50.01 ± 7.98 <.001
BMI 26.48 ± 4.51 29.99 ± 4.26 <.001
Cholesterol (mg/dL) 185.92 ± 36.54 199.55 ± 41.49 <.001
LDL (mg/dL) 115.11 ± 33.01 118.78 ± 38.27 <.001
TG (mg/dL) 111.38 ± 61.88 190.03 ± 109.86 <.001
HDL (mg/dL) 44.92 ± 10.37 39.68 ± 8.32 <.001
Glucose (mg/dL) 83.66 ± 26.64 106.38 ± 50.06 <.001
SBP (mmHg) 115.97 ± 15.33 130.56 ± 19.47 <.001
DBP (mmHg) 75.86 ± 9.92 83.99 ± 11.34 <.001
Uric acid (mg/dL) 4.49 ± 1.36 4.89 ± 1.41 <.001
UHR (mg/dL) 0.11 ± 0.04 0.13 ± 0.05 <.001
WC (cm) 91.21 ± 11.71 101.24 ± 9.84 <.001
hs-­CRP (mg/dL) 3.69 ± 8.50 4.85 ± 9.24 <.001

Abbreviations: BMI, body mass index; DBP, diastolic blood pressure; HDL, high-­density lipoprotein;
HTN, hypertension; hs-­CRP, high-­sensitive C-­reactive protein; LDL, low-­density lipoprotein; SBP,
systolic blood pressure; TG, triglyceride; UHR, uric acid to HDL ratio; WC, waist circumference.
*p-­value is computed based on t-­tests for continuous data and Chi-­squared test for categorical
data.

Subgroup analysis demonstrated that in the MetS (+) group, the main objective was to anticipate MetS using the LR model and to
there was a positive relationship between increasing number of determine MetS associated factors.
MetS components (i.e. the severity of MetS) and serum UA levels
(4.81 ± 1.36 vs. 5.01 ± 1.46 vs. 5.09 ± 1.53, respectively, p < .001)
as well as hs-­CRP levels (4.47 ± 8.71 vs. 5.40 ± 10.39 vs. 5.50 ± 8.11, 3.1 | LR model
respectively, p < .001). There was no significant difference be-
tween the group 2 and 3 in terms of UA (Table 2). HDL was signifi- Results from the multiple LR model revealed that variables includ-
cantly decreased when the MetS severity increased (40.62 ± 8.62 ing sex, TG, WC, HDL, glucose, SBP, DBP, HTN, UA, TC, DM and
vs. 38.54 ± 7.87 vs. 37.32 ± 6.62, respectively, p < .001). In addi- UHR were significantly associated with of the presence of MetS
tion, UHR was detected to be significantly lower in the MetS (−) (p < .002) (Table 3). In other words, our findings after adjusting the
group compared to the group 1, 2 and 3 (0.11 ± 0.04 vs. 12 ± 0.04, effect of other variables in the model, presented that the odds of
0.13 ± 0.05 and 0.14 ± 0.05, respectively, and p < .001). Group 1 having MetS in males is 0.14 times than that of females (p < .001).
had significantly lower UHR than group 2 and 3 (p < .001), whereas Also, after adjusting the effect of other variables for each increas-
there was no significant difference between the group 2 and 3 ing in UA, the odds of having MetS raised by 31% (p < .001) and for
(p = .33). a 10-­unit increase in UHR, the odds of having MetS decreased by
LR technique was used to investigate the relationship between 54% (p < .001). Among the analysed variables, UHR (OR 0.55; 95%
predictors and binary response variables (MetS [+] and MetS [−]). So, CI 0.38–­0.79), UA (OR 1.31; 95% CI 1.18–­1.47) and HTN (OR 2.01;
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KOLAHI AHARI et al. 5 of 9

TA B L E 2 Comparison of group 1, 2 and

Variables Group 1 Group 2 Group 3 p-­Value*
3 of MetS (+) population in terms of UHR,
UA, HDL and hs-­CRP. UHR 0.12 ± 0.04 0.13 ± 0.05*** 0.14 ± 0.05*** <.001
### ###
UA 4.81 ± 1.36 5.01 ± 1.46 5.09 ± 1.53 <.001
HDL 40.62 ± 8.62 38.54 ± 7.87 37.32 ± 6.62 <.001
Hs-­CRP 4.47 ± 8.71 5.40 ± 10.39 5.50 ± 8.11 <.001

Abbreviations: HDL, high-­density lipoprotein; hs-­CRP, high-­sensitive C-­reactive protein; UA, uric
acid.
*Used One way Anova test (variance analysis).; ***Group 2 and 3 were significantly different from
Group 1 (p-­value < .001).
###
Group 2 and 3 were significantly different from Group 1 (p-­value < 0.001).

TA B L E 3 The results of multiple LR model for the MetS (+) risk factors that appear to be directly promoting the development
group. of type 2 DM, adverse cardiovascular events and all-­cause mortal-

Source Longworth Odds ratio (95 %CI) p-­Value

ity. 24 MetS induces low-­grade chronic systemic inflammation in the
circulation and peripheral metabolic tissues, defined as ‘metabolic
Sex (Female) 158.128 0.14 (0.12, 0.16) <0.001
inflammation’, which is different from classical inflammation. 25,26
Male
Numerous studies confirmed that CRP as a conventional marker of
TG 148.778 1.01 (1.01, 1.02) <.001
systemic inflammation is correlated with the number of MetS com-
WC 140.938 1.07 (1.06, 1.08) <.001
ponents (i.e. MetS severity) and a higher CRP level was associated
HDL 65.793 0.87 (0.86, 0.88) <.001
with an increased incidence of cardiovascular events. 27 In accor-
Glucose 34.711 1.01 (1.01, 1.02) <.001
dance with previous studies, our study showed that serum hs-­CPR
SBP 20.559 1.03 (1.02, 1.03) <.001 level was significantly higher in the MetS (+) group and it was also
DBP 20.048 1.04 (1.03, 1.05) <.001 significantly increased with the number of MetS components. Nev-
HTN (HTN+) 15.603 2.01 (1.70, 2.37) <.001 ertheless, we found no statistically significant difference in term of
Uric acid 5.631 1.31 (1.18, 1.47) <.001 smoking status between the MetS (+) and MetS (−) groups. A study
Cholesterol 5.009 1.004 (1.003, 1.006) <.001 by Daniel et al. reported that not former smokers had significantly
UHR 2.723 0.55 (0.38, 0.79) .001 greater insulin resistance compared to non-­
smokers in a native
American population. 28 Hughes et al. reported that fasting insulin
Abbreviations: DBP, diastolic blood pressure; HDL, high-­density
lipoprotein; HTN, hypertension; SBP, systolic blood pressure; TG, levels did not significantly differ between smokers and non-­smokers
triglyceride; UHR, uric acid to HDL ratio; WC, waist circumference. in a random sample of males aged 30–­69 years from the general pop-
ulation of Singapore. 29 This could be in agreement with the finding
95% CI 1.70–­2.37) had the greatest associations with MetS. In ad- that smoking less than 10 cigarettes per day was not an independent
dition, Figure 2 shows the comparison between UHR, UA, HDL and risk factor for MetS in either gender.30
hs-­CRP and group 1, 2 and 3 of MetS (+) population. Moreover, in The relationship between serum UA levels and MetS has been
order to determine the sensitivity and specificity of UHR, receiver well demonstrated in the literature. According to numerous studies,
operating characteristic (ROC) curve analysis was performed. The there is a positive association between serum UA and the prevalence
optimum cutoff was 9.5% with sensitivity 89.07%, specificity 77.03% of MetS. Furthermore, serum UA level was elevated significantly as
and accuracy 84.30% (area under ROC [AUC] 92.17%) (Figure 3). We the number of metabolic components increased.4,6,31,32,33 A higher
summarize the concept of the paper in graphical abstract (Figure 4). level of serum UA is also an independent and strong factor for de-
veloping and predicting MetS in healthy middle-­aged population
of both gender.34,35 In subjects with elevated serum UA levels, the
4 | DISCUSSION risk of incident type 2 DM is also increased.36,37 In Iran, it has been
reported that those with MetS have higher serum UA levels com-
To the best of our knowledge, this is the first study conducted on pared to those without MetS.33,38 Safiri et al. reported that the as-
possible association between UHR and severity of MetS in a large sociation of serum UA with some components of MetS may indicate
population. Our study showed that UHR was significantly higher in that serum UA might be an additional component of MetS in ado-
the MetS (+) group compared to the MetS (−) population. Subgroup lescents.38 Our results are confirmatory to previous findings. In our
analysis showed a correlation between the increases in the number study, serum UA level was significantly higher in those with MetS;
of MetS criteria along with the increase in the UHR, serum UA and moreover, serum UA increased as the number of criteria (severity)
hs-­CRP. of MetS increased.
MetS is a tremendously growing public health problem, which HDL has anti-­
inflammatory, antioxidant and atheroprotective
is comprised of interconnected and heterogeneous metabolic origin properties with mitigates endothelial dysfunction through reverse
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6 of 9 KOLAHI AHARI et al.

F I G U R E 2 Comparison between
UHR (A), UA (B), HDL (C) and hs-­CRP
(D) and group 1, 2 and 3 of MetS (+)
population. hs-­CRP, high-­sensitive
C-­reactive protein; HDL, high-­density
lipoprotein; UA, uric acid; UHR, uric acid
to HDL ratio.

F I G U R E 3 ROC curve of UHR in

determining MetS. ROC, receiver
operating characteristic; UHR, uric acid to
HDL ratio.
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KOLAHI AHARI et al. 7 of 9

F I G U R E 4 The primary findings of present study.

cholesterol transport.39 HDL functionality has been reported to be In a study on 4551 patients diagnosed with type 2 DM in Shang-
negatively and independently associated with the risk of developing hai, a positive correlation between UHR and diabetic macrovascular
CVD.12 Our study showed that people with low HDL level were more and microvascular complications such as CVD and chronic kidney
likely to develop MetS than with normal HDL cholesterol, which is disease (CKD) was observed in men and postmenopausal women,
consistent with previous studies.40,41 Furthermore, mean level of which may show the importance of measuring and lowering UHR
HDL significantly decreased as the number of components (severity) level in a timely manner to prevent diabetic nephropathy. However,
of MetS increase. As mentioned before, UHR is a novel inflammatory no correlation was observed between the prevalence of diabetic ret-
and metabolic marker, which increases in inflammatory conditions.13 inopathy and UHR level.46
The diagnostic role of UHR was first described by Kocak et al. in The relationship between UHR and MetS has been investigated
15
patients with MetS. Then, an increased UHR levels has been dis- in few studies before. Kocak et al. pointed out that UHR could pre-
cussed in other metabolic and inflammatory conditions. Zhang et al. dict MetS better than all five MetS criteria and could use as a new
showed that UHR was an independent risk factor of non-­alcoholic a inflammatory marker.15 Then, Aktas et al. reported that UHR was
fatty liver disease (NAFLD) among lean adults population who had significantly and positively associated with fasting plasma glucose
42
normal range of HDL and UA. Conformingly, Zhu et al. demon- (FPG) and HbA1c in men with type2 DM, so the study suggested that
strated the association between UHR and onset of NAFLD in non-­ UHR could serve as a promising predictor of diabetic control.14 A
obese Chinese population with normal lipid profile, in which higher study conducted on 817 people in 2021, reported that UHR is useful
UHR values were independently associated with increasing risk of in diagnosis of MetS and can also be used to screen subjects at risk
43
NAFLD occurrence. In a retrospective cross-­sectional cohort study of MetS.40 However, in that study, the relationship between UHR
of 535 subjects by Aktas et al., a Higher level of UHR in hyperten- and MetS severity was not evaluated. In the present study, we found
sive patients with poor-­controlled blood pressure (considered as SBP a significant positive association between UHR and MetS. Further-
≥140 or DBP ≥90 mmHg) was observed compared to those with well-­ more, we identified that the mean levels of UHR in subgroups of the
controlled blood pressure and healthy subjects. Moreover, UHR had MetS (+) group increased with increasing MetS components, indi-
considerably high sensitivity and specificity in detecting HTN pa- cating that patients with MetS generally have higher serum UA level
tients with poor-­controlled blood pressure and it was correlated with and lower HDL cholesterol level. This study is the first clinical study,
both SBP and DBP, as well as serum creatinine, estimated glomerular which demonstrates a significant positive association between UHR
44
filtration rate (eGFR), TG and BMI. Mansiroglu et al. reported that and MetS severity. Another strength of present study is the large
UHR was significantly elevated in patients with coronary fistula com- population included. One of the limitations of the present study is its
pared to the control group. Moreover, end diastolic measurement of retrospective design, which could cause selection bias. We also did
the right ventricle was significantly higher in patients with fistula.45 not exclude patients with comorbidities such as DM. Nevertheless,
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8 of 9 KOLAHI AHARI et al.

conspiracy between adipose tissue and phagocytes. Clin Chim Acta.

we suggest conducting prospective studies with other statistical 2019;496:35-­4 4.
methods to assess the association between UHR and MetS, in future. 4. Ali N, Miah R, Hasan M, et al. Association between serum uric acid
and metabolic syndrome: a cross-­sectional study in Bangladeshi
adults. Sci Rep. 2020;10(1):7841.
5. Jeong J, Suh YJ. Association between serum uric acid and metabolic
5 | CO N C LU S I O N syndrome in Koreans. J Korean Med Sci. 2019;34(48):e307.
6. Goncalves J, Oliveira A, Severo M, Santos A, Lopes C. Cross-­
The present study showed that among Iranian adult population, sectional and longitudinal associations between serum uric acid
there is a significant positive correlation between UHR level as a and metabolic syndrome. Endocrine. 2012;41:450-­457.
7. Meshkani R, Zargari M, Larijani B. The relationship between uric
novel easy-­
to-­
assess inflammatory and metabolic indicator and
acid and metabolic syndrome in normal glucose tolerance and nor-
MetS. Furthermore, there is a positive association between UHR mal fasting glucose subjects. Acta Diabetol. 2011;48:79-­88.
and MetS severity. 8. Heidelbaugh JJ. Lipid Disorders: A Multidisciplinary Approach, Clinics
Collections. 1st ed. Elsevier Health Sciences; 2015.
9. Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA. The HDL
AU T H O R C O N T R I B U T I O N S
hypothesis: does high-­density lipoprotein protect from atheroscle-
Rana Kolahi Ahari: Conceptualization (equal); writing –­original draft rosis? J Lipid Res. 2010;51(8):2058-­2073.
(equal). Amin Mansoori: Conceptualization (equal); formal analysis 10. Xepapadaki E, Nikdima I, Sagiadinou EC, Zvintzou E, Kypreos KE.
(equal). Toktam Sahranavard: Writing –­review and editing (equal). HDL and type 2 diabetes: the chicken or the egg? Diabetologia.
2021;64(9):1917-­1926.
Monireh Sadat Miri: Writing –­original draft (equal). Sara Feizi: Writ-
11. Liu R, Peng Y, Wu H, et al. Uric acid to high-­density lipoprotein cho-
ing –­original draft (equal). Majid Ghayour-­Mobarhan: Project ad- lesterol ratio predicts cardiovascular mortality in patients on peri-
ministration (equal). toneal dialysis. Nutr Metab Cardiovasc Dis. 2021;31(2):561-­569.
12. Aghasizadeh M, Samadi S, Sahebkar A, et al. Serum HDL choles-
terol uptake capacity in subjects from the MASHAD cohort study:
AC K N O​W L E D
​ G E ​M E N T S
its value in determining the risk of cardiovascular endpoints. J Clin
We would like to thank the participants of the MASHAD cohort Lab Anal. 2021;35(6):e23770.
study and colleagues in the Mashhad University of Medical Sciences 13. Kurtkulagi O, Tel BMA, Kahveci G, et al. Hashimoto's thyroiditis is
who helped us recruit and examine the study participants. associated with elevated serum uric acid to high density lipoprotein-­
cholesterol ratio. Rom J Intern Med. 2021;59(4):403-­4 08.
14. Aktas G, Kocak MZ, Bilgin S, Atak BM, Duman TT, Kurtkulagi
F U N D I N G I N FO R M AT I O N
O. Uric acid to HDL cholesterol ratio is a strong predictor of di-
This research did not receive any specific grant from funding agen- abetic control in men with type 2 diabetes mellitus. Aging Male.
cies in the public, commercial or not-­for-­profit sectors. 2020;23(5):1098-­1102.
15. Kocak MZ, Aktas G, Erkus E, Sincer I, Atak B, Duman T. Serum
uric acid to HDL-­cholesterol ratio is a strong predictor of met-
C O N FL I C T O F I N T E R E S T S TAT E M E N T
abolic syndrome in type 2 diabetes mellitus. Rev Assoc Med Bras.
Not applicable. 2019;65:9-­15.
16. Yao S, Zhou Y, Xu L, et al. Association between hyperuricemia and
DATA AVA I L A B I L I T Y S TAT E M E N T metabolic syndrome: a cross-­sectional study in Tibetan adults on
the Tibetan plateau. Front Endocrinol. 2022;13:964872.
The data that support the findings of our study are available from
17. Ghayour-­Mobarhan M, Moohebati M, Esmaily H, et al. Mashhad
the corresponding author upon reasonable request. The data are not stroke and heart atherosclerotic disorder (MASHAD) study: design,
publicly available due to ethical or privacy restrictions. baseline characteristics and 10-­year cardiovascular risk estimation.
Int J Public Health. 2015;60:561-­572.
18. Ford ES. Prevalence of the metabolic syndrome defined by the
E T H I C S S TAT E M E N T
International Diabetes Federation among adults in the US. Diabetes
All participants included in the study were informed about the study Care. 2005;28(11):2745-­2749.
and signed a written informed consent form before inclusion. The 19. Ghazizadeh H, Shakour N, Ghoflchi S, et al. Use of data mining ap-
study was approved by the Ethic Committee of Mashhad University proaches to explore the association between type 2 diabetes melli-
tus with SARS-­CoV-­2. BMC Pulm Med. 2023;23:1-­14.
of Medical Sciences.
20. Mansoori A, Hosseini ZS, Ahari RK, et al. Development of data min-
ing algorithms for identifying the best anthropometric predictors
ORCID for cardiovascular disease: MASHAD cohort study. High Blood Press
Habibollah Esmaily https://orcid.org/0000-0003-4139-546X Cardiovasc Prev. 2023;30:243-­253.
21. Mansoori A, Sahranavard T, Hosseini ZS, et al. Prediction of type
2 diabetes mellitus using hematological factors based on machine
REFERENCES
learning approaches: a cohort study analysis. Sci Rep. 2023;13:663.
1. Fahed G, Aoun L, Bou Zerdan M, et al. Metabolic syndrome: up- 22. Saberi-­Karimian M, Mansoori A, Bajgiran MM, et al. Data mining
dates on pathophysiology and management in 2021. Int J Mol Sci. approaches for type 2 diabetes mellitus prediction using anthropo-
2022;23(2):786. metric measurements. J Clin Lab Anal. 2023;37:e24798.
2. Ruiz-­Ojeda FJ, Olza J, Gil Á, Aguilera CM. Oxidative Stress and 23. Saberi-­Karimian M, Safarian-­Bana H, Mohammadzadeh E, et al.
Inflammation in Obesity and Metabolic Syndrome. Elsevier; 2018:1-­15. A pilot study of the effects of crocin on high-­density lipoprotein
3. Reddy P, Lent-­ Schochet D, Ramakrishnan N, McLaughlin M, cholesterol uptake capacity in patients with metabolic syndrome: a
Jialal I. Metabolic syndrome is an inflammatory disorder: a randomized clinical trial. Biofactors. 2021;47:1032-­1041.
 |

23989238, 2023, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/edm2.446 by Turkey Cochrane Evidence Aid, Wiley Online Library on [30/04/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
KOLAHI AHARI et al. 9 of 9

24. Hayden MR. Overview and new insights into the metabolic syn- 38. Safiri S, Qorbani M, Heshmat R, et al. Association of serum uric
drome: risk factors and emerging variables in the development acid with cardiometabolic risk factors and metabolic syndrome
of type 2 diabetes and cerebrocardiovascular disease. Medicina. in Iranian adolescents: the CASPIAN-­III study. Iran J Kidney Dis.
2023;59(3):561. 2016;10(3):126-­134.
25. Chan KL, Cathomas F, Russo SJ. Central and peripheral inflamma- 39. Natarajan P, Ray KK, Cannon CP. High-­density lipoprotein and cor-
tion link metabolic syndrome and major depressive disorder. Phys onary heart disease: current and future therapies. J Am Coll Cardiol.
Ther. 2019;34(2):123-­133. 2010;55(13):1283-­1299.
26. van de Vyver M. Immunology of chronic low-­ grade inflam- 40. Yazdi F, Baghaei MH, Baniasad A, Naghibzadeh-­ Tahami A,
mation: relationship with metabolic function. J Endocrinol. Najafipour H, Gozashti MH. Investigating the relationship between
2023;257(1):e220271. serum uric acid to high-­density lipoprotein ratio and metabolic syn-
27. Devaraj S, Singh U, Jialal I. Human C-­reactive protein and the met- drome. Endocrinol Diabetes Metab. 2022;5(1):e00311.
abolic syndrome. Curr Opin Lipidol. 2009;20(3):182-­189. 41. Al-­Nozha M, Al-­Khadra A, Arafah MR, et al. Metabolic syndrome in
28. Daniel M, Cargo M. Association between smoking, insulin resis- Saudi Arabia. Saudi Med J. 2005;26(12):1918-­1925.
tance and β-­cell function in a North-­western First Nation. Diabet 42. Zhang Y-­N, Wang Q-­Q, Chen Y-­S, Shen C, Xu C-­F. Association
Med. 2004;21(2):188-­193. between serum uric acid to HDL-­cholesterol ratio and nonalco-
29. Hughes K, Choo M, Kuperan P, Ong C-­N, Aw T-­C . Cardiovascular risk holic fatty liver disease in lean Chinese adults. Int J Endocrinol.
factors in relation to cigarette smoking: a population-­based survey 2020;2020:1-­6.
among Asians in Singapore. Atherosclerosis. 1998;137(2):253-­258. 43. Zhu W, Liang A, Shi P, et al. Higher serum uric acid to HDL-­
30. Ishizaka N, Ishizaka Y, Toda E-­I, Hashimoto H, Nagai R, Yamakado cholesterol ratio is associated with onset of non-­alcoholic fatty
M. Association between cigarette smoking, metabolic syndrome, liver disease in a non-­obese Chinese population with normal blood
and carotid arteriosclerosis in Japanese individuals. Atherosclerosis. lipid levels. BMC Gastroenterol. 2022;22(1):196.
2005;181(2):381-­388. 44. Aktas G, Khalid A, Kurtkulagi O, et al. Poorly controlled hy-
31. Liu P-­W, Chang T-­Y, Chen J-­D. Serum uric acid and metabolic syn- pertension is associated with elevated serum uric acid to HDL-­
drome in Taiwanese adults. Metabolism. 2010;59(6):802-­8 07. cholesterol ratio: a cross-­sectional cohort study. Postgrad Med.
32. Bonakdaran S, Kharaqani B. Association of serum uric acid 2022;134(3):297-­3 02.
and metabolic syndrome in type 2 diabetes. Curr Diabetes Rev. 45. Mansiroglu AK, Cekici Y, Sincer I, Gunes Y. Serum uric acid and uric
2014;10(2):113-­117. acid to HDL-­cholesterol ratio in coronary artery fistulas. Ann Med
33. Nejatinamini S, Ataie-­Jafari A, Qorbani M, et al. Association be- Res. 2019;26(12):2771-­2775.
tween serum uric acid level and metabolic syndrome components. 46. Xuan Y, Zhang W, Wang Y, et al. Association between uric acid to
J Diabetes Metab Disord. 2015;14:1-­7. HDL cholesterol ratio and diabetic complications in men and post-
34. Sui X, Church TS, Meriwether RA, Lobelo F, Blair SN. Uric acid menopausal women. Diabetes Metab Syndr Obe. 2023;16:167-­177.
and the development of metabolic syndrome in women and men.
Metabolism. 2008;57(6):845-­852.
35. Chen J-­H, Hsieh C-­H, Liu J-­S, et al. The power of serum uric acid in
predicting metabolic syndrome diminishes with age in an elderly
How to cite this article: Kolahi Ahari R, Mansoori A,
Chinese population. J Nutr Health Aging. 2016;20:912-­917.
36. Krishnan E, Pandya BJ, Chung L, Hariri A, Dabbous O. Sahranavard T, et al. Serum uric acid to high-­density
Hyperuricemia in young adults and risk of insulin resistance, pre- lipoprotein ratio as a novel indicator of inflammation is
diabetes, and diabetes: a 15-­year follow-­up study. Am J Epidemiol. correlated with the presence and severity of metabolic
2012;176(2):108-­116.
syndrome: A large-­scale study. Endocrinol Diab Metab.
37. Woyesa SB, Hirigo AT, Wube TB. Hyperuricemia and metabolic
syndrome in type 2 diabetes mellitus patients at Hawassa univer- 2023;6:e446. doi:10.1002/edm2.446
sity comprehensive specialized hospital, South West Ethiopia. BMC
Endocr Disord. 2017;17:1-­8.