Gender Difference in the Association Between Serum Uric Acid Level and Metabolic Syndrome and Components: A Cross-Sectional Analysis Among Chinese Young Adults

This study aimed to investigate the associations between serum uric acid (SUA) levels and metabolic syndrome (MetS) and MetS components in Chinese young adults. A cross-sectional survey was conducted among 3044 young adults (1266 men and 1778 women). The anthropometric index, lipid prole, fasting blood glucose and SUA levels were measured. Male and female participants were grouped according to the quartiles of SUA level separately. Multiple logistic regression analyses were performed to evaluate the association of SUA quartiles with MetS and its components.


Background
Metabolic syndrome (MetS) is an increasing public health problem, including general or central adiposity, high blood pressure, hyperglycemia, and dyslipidemia 1 . The prevalence rates of MetS in China were 9.8% in men and 17.8% in women based on a survey conducted in 2000-2001 2 and the rates increased to 31.0% and 36.8%, respectively 3 . Epidemiological studies have reported that MetS with individual component is involved in various chronic diseases, such as cardiovascular diseases 4 , diabetes 5 and cancers 6 . Therefore, early intervention for MetS components is necessary to prevent the development of related diseases and reduce the public health burden worldwide.
Uric acid (UA) is the ultimate metabolite of purine compounds. Previous studies have shown that uric acid, as one of the strong antioxidants, can provide some type of protection against cell oxidative damage. However, overproduction or underexcretion of uric acid can lead to adverse consequences, such as hyperuricemia and gout, which contribute to essential disease burden and health loss 7 . Previous epidemiological studies have found an association of increased serum uric acid (SUA) levels and MetS in different populations [8][9][10] . Furthermore, studies have demonstrated that increased SUA level is an important marker for predicting the risk of developing MetS components, such as hypertension 11 , diabetes 12 , obesity 13 , and dyslipidemia 14 . Our previous study found that a signi cantly increasing trend existed in the body mass indices (BMI) across the SUA level quartiles (23.8 kg/m 2 , 24.8 kg/m 2 , 26.2 kg/m 2 , and 30.1 kg/m 2 ) 15 . However, most studies have focused on this relationship in adults.
It has been documented that lifestyle in early life may be a strong predictor of uric acid metabolism and the resulting disease risk 16 . Given the increased prevalence of MetS in the Chinese young adults, this study aimed to further evaluate the relationships between SUA and MetS components, including dyslipidemia, hypertension, and obesity among Chinese young adults.

Sample and procedure
This study was conducted from September to November 2018, all 3450 young adults from a medical school participated in the physical examination, with 3430 students participating in the survey (response rate: 99.42%). Excluded subjects were those who less than 18 years old (n=300), or missed height or weight (n=86), nally, 3044 eligible subjects were included in the nal analyses. The self-administrated questionnaire was completed by trained interviewers with demographic characteristics of gender, age, smoking and drinking status, physical activity, etc.

Anthropometric measurement
All participants received physical examinations; weight, height, waist circumference (WC), hip circumference (HC) and blood pressure were measured. The measurements were obtained from each participant by trained staff according to a standard protocol. Height, WC and HC were measured to the nearest 0.1 cm and weight to the nearest 0.1 kg by ultrasound height and weight measuring instrument (Shengyuan, China). Subjects were measured in socks or bare feet and light clothes. WC was measured 1cm above the umbilicus in a horizontal plane. HC was mea sured at the level of the maximal gluteal protrusion by using general tape. Waist-hip ratio (WHR) was calculated as WC divided by HC. Blood pressure was measured 2 times by Omron U30 electronic sphygmomanometer in the seated position after at least 5 minutes of rest and their average value was obtained for analysis. Obesity was de ned according to body mass index (BMI; weight (kg)/height (m) 2 ) based on Chinese-speci c criteria 17 . Accordingly, normal weight or underweight was de ned as BMI<23.9kg/m 2 , overweight as BMI of 24-27.9kg/m 2 and obesity as BMI≥28 kg/m 2 . At least 30 minutes duration of exercises per day, that caused heavy sweating or large increases in breathing or heart rate, was de ned as physical activity 18 . High physical activity was de ned as exercising 3 times or more per week.

De nition of MetS
The de nition of MetS was in accordance with the International Diabetes Federation and the American Heart Association criteria that the presence of any 3 of the following condition constitutes a diagnosis of MetS: WC for Asians ≥80 cm in women and ≥90 cm in men; systolic blood pressure(SBP) ≥130 mmHg or diastolic blood pressure(DBP) ≥85 mmHg; FPG ≥100 mg/dl; HDL-C <50 mg/dl in women and <40 mg/dl in men; TG level≥150 mg/dl 20 .

Statistical analysis
Continuous data were expressed by means ± standard difference (SD) and categorical variables by percentage. T-test and one-way ANVOA were used in continuous data analysis. Categorical variables distributions were compared by the Chi-square test and trend Chi-square test. Correlation analysis between SUA and continuous variables of MetS components were assessed by Pearson's correlation coe cient test. Multivariable logistic regressions were performed to evaluate the association of SUA and MetS and components to calculate odds ratios (ORs) and its 95% interval con dence (CI). SPSS 18.0 was used for statistical analysis (SPSS, Inc, Chicago, IL), and a P value <0.05 was de ned to be statistically signi cant.

Results
Baseline characteristics of this study A total of 3044 young adults were included in the nal data analysis. The mean age of the participants was 18.69 ± 0.95 years (range 18-26 years). Of the 3044 subjects, 1778 (58.41%) were females and the mean (± SD) age was 18.68 ± 0.95 years. The prevalence of MetS, hyperuricemia and high physical activity in males was signi cantly higher than that in females (P < 0.05). The males had signi cantly higher BMI, WC, HP, WHR, SBP, DBP, LDL-C and FPG levels but signi cantly lower HDL-C and TC levels than the females(P < 0.05). The demographic characteristics of all participants are summarized in Table 1. were presented in Table 2.  Table 3.

Association Between Sua And Mets And Mets Components
The prevalence of the MetS was too low among participants in the lowest quartile (cases = 0) of the serum concentration of the uric acid. Therefore, we collapsed the 2 lowest quartiles of uric acid into a single reference group. In females, compared with the lowest 2 quartiles, the SUA was categorized in the 3rd quartile and the highest quartile showed a positive association with abdominal obesity prevalence after adjustment for age, obesity and the other components of the MetS as dichotomized variables, with the OR (95% CI) were 1.976(1.128-3.459) and 1.766(1.020-3.057), respectively. The data were presented in Table 4.

Discussion
In this cross-sectional study, the overall prevalence rate of hyperuricemia was 29.7%, which was signi cantly more common in males than in females (47.6% vs. 17%). This rate was higher than those in most Asian epidemiological studies: Bangladesh, 9.3% 21 ; Japan, 25.8% 22 ; and Thailand, 10.6% 23 . These disparities may be attributable to racial or ethnic differences. A more recent Thai study reported that the prevalence of hyperuricemia in men has reached 59% 24 . Age differences may also partly explain this phenomenon. In the present study, the participants were young adults In a Spanish study, the prevalence rate of hyperuricemia in children was 53% 25 . In China, students had high-intensity learning and accompanying high nutrition, including plenty of purine-rich foods in senior high school, which may lead to increased uric acid level and weight gain.
The results of the present study showed that the prevalence of MetS increased linearly in the quaternion of SUA, which con rmed the strong association between SUA level and MetS in Chinese young adults. These results were consistent with several epidemiological studies which reported in Asian population 9,10 , European population 14,26 , North American population 27 . After adjustment for confounding factors, SUA remained a risk factor for MetS in males. Low prevalence of MetS in the young participants may explain the possible reason. In a longitudinal study on Taiwanese adults, SUA seems an important predictor for the risk of incident MetS in 30-40 years but not in 20-30 years age groups 28 . The mechanism for the positive association between SUA levels and MetS has not been fully elucidated, but some studies have suggested several possible explanations. Xanthine oxidoreductase (XOR) is a key enzyme in the formation of UA. It may participate in the pathogenesis of metabolic syndrome through oxidative stress and in ammation induced by XOR derived reactive oxygen species and UA 29 . Animal experiments showed that XOR knockout mice could not produce UA, which led to the defect of fat accretion, suggesting that UA is involved in the adipogenesis 30 . Hyperuricemia has been demonstrated to impair nitric oxide generation and subsequent endothelial dysfunction 31 . Another important mechanism may be that hyperuricemia involved in insulin resistance through the production of reactive oxygen species and De ciency of endothelial-formed nitric oxide 32 .
In addition, a positive association of SUA levels with low HDL-C and high TG was observed independent sex. However, the association with low HDL-C was no longer signi cant, whereas associated with high TG in males in multivariable regressions. This nding was partly similar to that of previous study which conducted among US children and adolescents 33 . In a survey of 234 male seafarers, SUA levels was associated with MetS and high TG 34 . Studies on the association between SUA levels and dyslipidemia were primarily conducted in elderly or middle-aged adults even though the results were controversial [35][36][37] . However, these results were likely to be disturbed by other confounding factors, such as chronic cardiovascular diseases and long-term medication. This observation indicated that SUA level might be a biomarker in the development of high TG in males.
Our results further found an association between SUA levels and abdominal obesity in females. The nding, which was more relevant to women, was similar to a Japanese study 38 . As we know, abdominal obesity is characterized by accumulation of visceral fat. Hikita et al. 39 reported that SUA level was positively correlated with visceral fat area and subcutaneous fat area. According to a recent study, saliva UA has been proved to be an important marker of fat accumulation in adolescents 40 . Hyperuricemia reduces serum leptin levels, thereby inhibiting the decomposition of visceral fat and increasing the accumulation of TG in non-adipocytes, promoting the development of obesity 41 . Rats model experiments indicated that inhibition of UA production could block the conversion of fructose to TG in hepatocytes and reduce the accumulation of TG 42 . It is suggested that the increase of SUA level is involved in the occurrence and development of abdominal obesity.
Of the MetS components, high blood pressure showed an increased prevalence across the SUA levels in males, but the difference failed to reach statistical signi cance adjustment for other MetS components. This result is different from that shown by a 5-year cohort study, which indicated that hyperuricemia was associated with increased incidence rates of hypertension 43 . The difference might be attributed to the different subjects that subjects in our study were younger (18 to 26 years) than the reported study (30 to 85 years). Additionally, we adjusted abdominal obesity, hyperglycemia, high TG and low HDL-C that maybe interferes or modify this relationship. A Japanese cross-sectional study revealed that serum TG level may interfere with the relationship between SUA and prehypertension 44 . These results suggest that, if there are other metabolic factors or interactions interfere with or alter this relationship.
Our results should be interpreted in the context of potential limitations. Firstly, as it is a cross-sectional study, this study cannot prove the causal relationship between SUA and MetS and its components. Therefore, more prospective studies need to be conducted. Secondly, as the subjects of this study were young adults, the prevalence of hyperglycemia in females was 1.12% and 0.87% in males, and the prevalence of MetS in the total subjects was 2%. This low prevalence may affect the con dence of the results. Finally, this study was conducted in a medical university and may not be applicable to other ethnic populations.

Conclusions
In present study, we con rmed that SUA level was positively associated with the prevalence of MetS and high TG in young male adults. In females, SUA was signi cantly associated with the prevalence of abdominal obesity. Additionally, more attention is necessary to examine the role of SUA in the pathogenesis of MetS. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.