Contribution of Nontraditional Lipid Proles to Hyperuricemia in Rural Chinese Hypertensive Population: Findings From the China Hypertension Registry Study

Background: Current studies support nontraditional lipid proles [total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio, triglyceride (TG)/HDL-C ratio, low-density lipoprotein cholesterol (LDL -C)/HDL-C ratio, non-HDL-C] as reliable indicators of cardiovascular disease, stroke and diabetes. However, whether nontraditional lipid proles can be used as reliable markers for hyperuricemia (HUA) remains unclear due to limited research. The present study investigated the relationship of nontraditional lipid proles with HUA in hypertensive patients. Methods: We analyzed data from 13,721 Chinese hypertensive population untreated with lipid-lowering drugs. The relationship between non-traditional lipid proles and HUA was examined by multivariate logistic regression analysis and smooth curve tting (penalized spline method). Results: The results showed that there were positive associations of TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C with HUA, respectively (all P <0.001). Furthermore, nontraditional lipid proles were converted from continuous variables to tertiles. Compared with lowest tertile, the multivariate adjusted ORs (95% CI) of TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio and non-HDL-C in highest tertile were 1.79 (1.62, 1.99), 2.09 (1.88, 2.32), 1.67 (1.51, 1.86), 1.93 (1.74, 2.13), respectively (all P <0.001). Conclusions: In Chinese hypertensive population, there were positive associations between nontraditional lipid proles (TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C) and HUA. Our ndings further expand the scope of application of nontraditional lipid proles. CHD, coronary heart disease; BMI, index; SBP, blood pressure; TC,


Background
Hyperuricemia (HUA) is a metabolic abnormality syndrome caused by disorders of purine metabolism [1].
Previous studies have shown that HUA is an independent risk factor for metabolic syndrome, chronic kidney disease (CKD), hypertension, cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and death [2,3].Epidemiological studies show that the overall prevalence of HUA in China was 13.3% [4], and the prevalence of HUA was signi cantly higher in hypertensive patients [5].The dramatically increasing prevalence of HUA is a great challenge to public health concerns and constitutes a serious socioeconomic burden [6].Hence, identifying HUA-related risk factors in hypertension population and nding potential valuable indicators, could help to improve the management and treatment strategy of chronic diseases.
Previous studies have reported that HUA was associated with higher levels of TC, TG and LDL-C, and lower levels of HDL-C [7,8].However, the fact is that most HUA patients usually have multiple disorders of lipid metabolism [9,10], so a single lipid may not be an effective indicator of HUA.Recently, there is increasing evidences that nontraditional lipid pro les, represented TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C, are valuable and excellent markers of CVD, T2DM, CKD and all-cause mortality [11][12][13][14].HUA, as an independent risk factor for CKD, CVD and all-cause mortality, plays an important role in the occurrence and progression of these diseases [15,16].Therefore, there may be relationships between nontraditional lipid pro les and HUA.However, to date, there is limited information on the association between these four nontraditional lipid pro les and HUA in Chinese population.In addition, more than 1/3 of hypertensive patients have HUA, and these two diseases have a synergistic effect on the occurrence and development of CVD and death [17,18].Therefore, the present study aims to investigate the independent relationships between four nontraditional lipids pro les and HUA in rural Chinese hypertensive population.

Study design and participants
The data we analyzed came from the Chinese Hypertension Registry Study (http://www.chictr.org.cn/,No: ChiCTR1800017274), and details about the purpose, protocol, and outcome of the study have been described [19].The inclusion and exclusion criteria for the study are described in detail in Table S1.In short, this study is a large observational cohort study of patients with hypertension.The aim of the study was to explore the prevalence of hypertension in China and the risk factors that in uence its treatment and prognosis.Hypertension was de ned as Systolic blood pressure (SBP) values ≥140 mmHg and/or diastolic BP (DBP) values ≥90 mmHg, self-report history of hypertension, or the use of antihypertensive drug(s) at baseline [20].From March to August 2018, a total of 14,268 patients with hypertension were recruited into our study in Wuyuan, Jiangxi Province, China, and all study participants signed informed consent before being recruited into the study.In our study, we excluded participants who were not treated with lipid-lowering drugs and nally analyzed data from 13,721 hypertensive patients.The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Anhui Medical University Biomedical Institute (No. CH1059).

Data collection
In the current study, staffs with physician quali cations collected venous fasting blood for each study participant.The collected blood samples were frozen and transported to the Biaojia Biotechnology Laboratory in Shenzhen, China.Laboratory staff tested the biochemical indicators in the blood samples by an automatic clinical analyzer (Beckman Coulter, USA).Laboratory indicators include lipids, liver function, renal function, Hcy, blood glucose.Details of biochemical indicators were shown in Table 1.Body mass index (BMI) was calculated by dividing weight by the square of height (kg/m2).After a 10minute rest, each participant's blood pressure and heart rate were measured by an electronic sphygmomanometer.Other covariates were obtained through questionnaires, including age, sex, smoking and drinking status, disease and medication history.The speci c contents of the questionnaire were presented in Table 1.
De nition of nontraditional lipid pro les and HUA The nontraditional lipid pro les represented TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio and non-HDL-C [13,14,21,22].The TC/HDL-C, TG/HDL-C and LDL-C/HDL-C ratios were calculated as TC, TG, LDL-C divided by HDL-C, respectively.Non-HDL-C was calculated as HDL-C subtracted from TC.To date, eight guideline documents recommended that serum uric acid level >420 μmol/L (7 mg/dL) was diagnosed as HUA, regardless of sex [23][24][25].According to the updated Chinese guidelines, HUA in our study was de ned as serum uric acid level >420 μmol/L (7 mg/dL), regardless of gender [25].

Statistical analysis
Baseline characteristics of the study population were displayed according to with or without HUA.
Continuous variables are presented as the mean ± SD and categorical variables are presented as percentage (%).Logistic regression analyses models were performed to assess the association of nontraditional lipid pro les (TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C) with HUA by presenting the odds ratio (OR) and 95% con dence interval (CI) after adjusting for confounding factors.The trend test was used to evaluate the linear relationship between nontraditional lipid pro les and HUA, when nontraditional lipid pro les used as tertiles.Fully adjusted smoothing curve tting (penalized spline method) visually demonstrated the relationship between nontraditional lipid pro les and HUA.

Results
Baseline characteristics of the study participants A total of 13,721 hypertensive patients untreated lipid-lowering drugs were included in our analysis (mean age: 63.79 ± 9.41 years; 47.23% males) (Fig. 1).The distributions of study participant baseline characteristics according to the status of HUA (non-HUA and HUA) were presented in Table 1.Compare with non-HUA group, HUA group had higher values for age, male, current smoking, alcohol use, CHD, diabetes mellitus, antihypertensive drugs, BMI, DBP, TC, TG, LDL-C, TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, non-HDL-C, Hcy and FBG, and lower values for SBP, HDL-C and eGFR (all P <0.05).
Relationship between nontraditional lipid pro les and HUA Fig. 2 showed the results of smooth curves between four nontraditional lipids pro les and HUA.Fig. 2A, 2B, 2C and 2D showed the positive associations of TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio and non-HDL-C with HUA, respectively.Table 2 showed the results of multiple logistic regression analysis of the relationship between nontraditional lipid pro les and HUA.In the crude and adjusted model, there were positive associations of TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C with HUA, respectively (all P <0.001).

Discussion
In this large sample of Chinese hypertensive population, the constellation of our ndings offered novel evidence for an independent positive association of nontraditional lipid pro les (TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C) with HUA.Our ndings suggest that detection of nontraditional lipid pro les may be bene cial for the prevention and treatment of HUA.
Increasing evidence suggested that nontraditional lipid pro les could be a valuable indicator for a variety of diseases.Guo et al. [13] included 5,782 patients with hypertension (mean age: 57±10 years) for analysis, and found that higher TC/HDL-C, TG/HDL-C and LDL-C/HDL-C ratio were associated with higher risk of ischemic stroke, while non-HDL-C was not associated with ischemic stroke.Wang et al. [22] analyzed data from 3,259 patients with hypertension (mean age: 58.78 ± 10.20 years), and found that nontraditional lipid pro les were positively correlated with reduced eGFR.Wang et al. [21] analyzed data of 10,756 Chinese (mean age: 53.8 years) and found that nontraditional lipid pro les were positively correlated with CVD risk.Wang et al. [14] analyzed the data of 2,944 hypertensive patients (mean age: 57.09 ± 11.29 years), indicating that the nontraditional lipid pro les were signi cantly positively associated with diabetes, and further found that TG/HDL-C ratio was more signi cantly correlated with diabetes.Therefore, we have su cient reasons to believe that nontraditional lipid pro les are effective indicators of these diseases, including stroke, CVD, diabetes, CKD.It is noteworthy that HUA plays an important role in the occurrence and development of the diseases mentioned above [3,24,26].Therefore, prevention and treatment of HUA have great clinical bene ts.However, to our knowledge, few studies have explored the relationship between nontraditional lipid pro les and HUA, so it is not clear whether nontraditional lipid pro les can serve as valuable markers of HUA.Our ndings extend the application of nontraditional lipids and well ll in the gaps of previous studies, so this study has very important clinical signi cance.
There is a panel of plausible pathomechanisms responsible for the increased risk of HUA in those with poor nontraditional lipid pro les.It was widely-accepted that reduced renal function, in ammation, insulin resistance (IR), lifestyle and lipid-lowering drugs can induce HUA.Excessive lipids deposit on the intima, and mononuclear macrophages become foam cells by phagocytosis of lipids deposited on the intima, thus causing renal arteriosclerosis, resulting in reduced ltration function of the kidney, and thus reduced excretion of uric acid from the kidney, resulting in HUA production [27].Higher levels of TC/HDL-C and TG/HDL-C ratio may be mediated by CRP-mediated in ammatory response, leading to the occurrence of HUA [28,29].Higher lipids lead to IR through lipotoxicity, in ammation and endoplasmic reticulum stress, which in turn leads to the development of HUA.In addition, some researchers have found that hyperlipidemia and HUA patients share the same lifestyle and diet, such as excessive alcohol consumption and high-fat food intake, which also suggests that clinicians should conduct lipid-lowering and uric acid-lowering treatments simultaneously [30].Interestingly, Deedwania et al. found that lipidlowering drugs not only reduced lipid levels, but also reduced SUA in patients with CVD [31].There was a close relationship between nontraditional lipid pro les and HUA.However, current basic studies cannot fully elucidate the mechanism behind this relationship, and further basic experiments are needed to fully elucidate the speci c biological mechanism of this association.

Study Strengths Limitations
Our study has obvious strengths and some limitations.This study is currently the rst study to examine the association of nontraditional lipid pro les (TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C) with the risk of HUA in Chinese hypertension population.Nevertheless, some limitations should be noted.First, as a cross-sectional study, our results failed to provide causality regarding the relationship between nontraditional lipid pro les and HUA.Second, our study population is from Chinese hypertensive patients, so the generality of our conclusions is limited.

Conclusions
In rural Chinese hypertensive population, there were positive associations between nontraditional lipid pro les (TC/HDL-C ratio, TG/HDL-C ratio, LDL-C/HDL-C ratio, and non-HDL-C) and HUA.Our ndings further expand the scope of application of nontraditional lipid pro les.These novel and important results suggest that nontraditional lipid pro les can be used as potential and valuable indicators of HUA, and provide a new strategy for the prevention and treatment of HUA.

Table 1 .
Characteristics of Study Population