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1.  Longitudinal association between serum urate and subclinical atherosclerosis: the Coronary Artery Risk Development in Young Adults (CARDIA) study 
Journal of internal medicine  2013;274(6):10.1111/joim.12120.
The aim of the present study was to determine whether serum urate (sUA) concentration is positively associated with subclinical atherosclerosis, independent of body mass index (BMI), among generally healthy adults.
Design and setting
The CARDIA study followed 5115 black and white individuals aged 18–30 years in 1985–1986 (year 0). Subclinical atherosclerosis comprised coronary artery calcified plaque (CAC; years 15, 20 and 25) and maximum common carotid intima–media thickness (IMT; year 20). sUA (years 0, 10, 15 and 20) was modelled as gender-specific quartiles that were pooled. Discrete-time hazard regressions and generalized linear regressions were used for analyses.
Mean sUA concentration was lower in women than in men, and increased with age. Adjusting for demographic and lifestyle factors, the highest versus lowest quartile of sUA at year 0 was associated with a 44% [95% confidence interval (CI) 20%, 73%] greater risk of CAC progression from year 15 to 25 (Ptrend < 0.001), which was attenuated by adjustment for BMI at year 0 (Ptrend = 0.45). A stronger association was found between sUA at year 15 and CAC progression at year 20 or 25 (hazard ratio 2.07, 95% CI 1.66, 2.58 for the highest versus lowest sUA quartile Ptrend < 0.001), which was attenuated but remained significant with additional adjustment for BMI at year 15 (Ptrend = 0.01). A greater increment in sUA concentration from year 0 to year 15, independent of change in BMI, was related to a higher risk of CAC progression (Ptrend < 0.001). Similar associations were found between sUA and IMT, but only in men.
sUA may be an early biomarker for subclinical atherosclerosis in young adults; starting in early middle age, sUA predicts subclinical atherosclerosis independently of BMI.
PMCID: PMC3825786  PMID: 23952533
calcified plaque; intima–media thickness; subclinical atherosclerosis; urate; uric acid
2.  Serum Urate Is Not Associated with Coronary Artery Calcification: The NHLBI Family Heart Study 
The Journal of rheumatology  2010;38(1):111-117.
Urate may have effects on vascular remodeling and atherosclerosis. We had shown an association between serum uric acid (SUA) and carotid atherosclerotic plaques. Inflammation and vascular remodeling in atherosclerosis promote coronary artery calcification (CAC), a preclinical marker for atherosclerosis. Here, we examined whether SUA is associated with CAC, using the same study sample and methods as for our previous carotid atherosclerosis study.
The National Heart, Lung, and Blood Institute Family Heart Study is a multicenter study designed to assess risk factors for heart disease. Participants were recruited from population-based cohorts in the US states of Massachusetts, North Carolina, Minnesota, Utah, and Alabama. CAC was assessed with helical computed tomography (CT). We conducted sex-specific and family-cluster analyses, as well as additional analyses among persons without risk factors related to both cardiovascular disease and hyperuricemia, adjusting for potential confounders as we had in the previous study of carotid atherosclerosis.
For the CAC study, 2412 subjects had both SUA and helical CT results available (55% women, age 58 ± 13 yrs, body mass index 27.6 ± 5.3). We found no association of SUA with CAC in men or women [OR in men: 1.0, 1.11, 0.86, 0.90; women: 1.0, 0.83, 1.00, 0.87 for increasing categories of SUA: < 5 (referent group), 5 to < 6, 6 to < 6.8, ≥ 6.8 mg/dl, respectively], nor in subgroup analyses.
Replicating the methods used to demonstrate an association of SUA with carotid atherosclerosis did not reveal any association between SUA and CAC, suggesting that SUA likely does not contribute to atherosclerosis through effects on arterial calcification. The possibility that urate has divergent pathophysiologic effects on atherosclerosis and artery calcification merits further study.
PMCID: PMC3119360  PMID: 20889594
3.  Synergistic Effects of Serum Uric Acid and Cardiometabolic Risk Factors on Early Stage Atherosclerosis: The Cardiometabolic Risk in Chinese Study 
PLoS ONE  2012;7(12):e51101.
To comprehensively examine the associations of serum uric acid (SUA) with central and peripheral arterial stiffness in Chinese adults, and particularly assess the interactions between SUA and other cardiometabolic risk factors.
The study included 3,772 Chinese men and women with carotid radial pulse wave velocity (crPWV), carotid femoral PWV (cfPWV), carotid artery dorsalis pedis PWV (cdPWV) and SUA measured.
After adjustment for age, sex, and BMI, the levels of SUA were significantly associated with increasing trend of cfPWV, crPWV and cdPWV (P for trend <0.0001). Further adjustment for heart rate (HR), blood pressure (BP) and lipids attenuated the associations with crPWV and cdPWV to be non-significant (P = 0.1, P = 0.099 respectively), but the association between SUV and cfPWV remained significant (P = 0.004). We found significant interactions between SUA and HR or BP in relation to cfPWV (P for interaction = 0.03, 0.003 respectively). The associations between SUA and cfPWV were more evident among individuals with higher HR or normal BP than those with lower HR or hypertension.
SUA was associated with elevated aortic arterial stiffness in Chinese adults, independent of conventional cardiovascular risk factors. BP and HR might modify the deleterious effects of SUA.
PMCID: PMC3524235  PMID: 23284659
4.  Serum Uric Acid Is Associated with Carotid Plaques: The National Heart, Lung, and Blood Institute Family Heart Study 
The Journal of rheumatology  2009;36(2):378-384.
To examine the association of serum uric acid (SUA) with a marker of preclinical cardiovascular disease (CVD), carotid atherosclerotic plaques (PLQ), where early evidence of risk may be evident, focusing on individuals without CV risk factors.
The National Heart, Lung, and Blood Institute Family Heart Study is a multicenter study designed to assess risk factors for heart disease. PLQ were assessed with carotid ultrasound. We conducted sex-specific logistic regression to assess the association of SUA with presence of PLQ, including analyses among persons without risk factors related to both CVD and hyperuricemia.
In total, 4866 participants had both SUA and carotid ultrasound assessed (54% women, mean age 52 yrs, mean body mass index 27.6). The association of SUA with PLQ increased with increasing SUA levels, demonstrating a dose-response relation for men [OR 1.0, 1.29, 1.61, 1.75, for SUA categories < 5 (reference), 5 to < 6, 6 to < 6.8, ≥ 6.8 mg/dl, respectively; p = 0.002]. Similar associations were found in men without CV risk factors. We found no relation of SUA with PLQ in women.
In this large study, SUA was associated with carotid atherosclerotic plaques in men. Results were similar in the absence of CV risk factors. These results suggest that SUA may have a pathophysiologic role in atherosclerosis in men. (J Rheumatol First Release Nov 15 2008; doi:10.3899/jrheum.080646)
PMCID: PMC2731484  PMID: 19012359
5.  Relationship Between Serum Uric Acid Levels, Metabolic Syndrome, and Arterial Stiffness in Korean 
Korean Circulation Journal  2010;40(7):314-320.
Background and Objectives
Associations have been reported between the serum uric acid (SUA) level, metabolic syndrome (MS), and atherosclerosis. We have determined the relationship between the SUA level, MS, and arterial stiffness in Korean.
Subjects and Methods
Cross-sectional data from 1,276 adults who underwent routine laboratory tests and pulse wave velocity (PWV) measurements during a health check-up were analyzed in a gender-specific manner. None of the participants had atherosclerotic cardiovascular disease, diabetes, renal disease, or systemic disease, or were under treatment which would affect SUA levels, or taking medications for hypertension or dyslipidemia.
After adjustment for age, smoking status, total cholesterol (TC), and creatinine, the odds ratios (ORs, 95% confidence interval) of gender-specific quartiles of SUA for MS were 1.0, 1.28 (0.66-2.47), 1.46 (0.76-2.82), and 2.21 (1.15-4.26) in females, and 1.0, 1.33 (0.82-2.17), 1.60 (0.96-2.66), and 2.03 (1.21-3.40) in males. However, after adjustment for waist circumference, there were no significant differences in the ORs among the SUA quartile groups in females and males (both, p=NS). The Pearson's correlation coefficients for the relationship between SUA levels and heart-femoral (hf) PWVs or brachial-ankle (ba) PWVs were not significant in females and males (r=0.054 and r=0.015, respectively, in females; r=-0.036 and r=-0.015, respectively, in males; all, p=NS).
An elevated SUA level is associated with abdominal obesity among the MS components, but the SUA level is not associated with PWV in females or males.
PMCID: PMC2910287  PMID: 20664739
Uric acid; Metabolic syndrome
6.  Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study 
Our purpose was to test the hypothesis that hyperuricemia is associated with coronary artery calcification (CAC) among a relatively healthy population, and that the extent of calcification is directly proportional to the serum uric acid (sUA) concentration.
Data from 2,498 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed using logistic regression models. Subjects were free of clinical heart disease, diabetes, and renal impairment. The main measure was the presence of any CAC by computerized tomography (Agatston score >0).
Forty-eight percent of the study participants were male and 45% were African-American. Mean (± SD) age was 40 ± 4 years, body mass index 28 ± 6 kg/m2, Framingham risk score -0.7 ± 5%, blood pressure 113 ± 14/75 ± 11 mmHg, alcohol consumption 12 ± 27 ml/day, and sUA 297 ± 89 μmol/L (5.0 ± 1.5 mg/dL). Prevalence of CAC increased with sUA concentration among both men and women. Adjusted for age, gender, race, lipoproteins, triglycerides, smoking, blood pressure, presence of metabolic syndrome, C-reactive protein, waist circumference, alcohol use, creatinine, and serum albumin, the highest quartile of sUA (>393 μmol/L [6.6 mg/dL] for men and >274 μmol/L [4.6 mg/dL] for women) was associated with an odds ratio of 1.87 (1.19-2.93) compared to the lowest quartile (<291 μmol/L [4.9 mg/dL] for men and <196 μmol/L [3.3 mg/dL] for women). Among those with any CAC, each unit increase in sUA was associated with a 22% increase in Agatston score (P = 0.008) after adjusting for the above covariates.
Hyperuricemia is an independent risk factor for subclinical atherosclerosis in young adults.
PMCID: PMC3132061  PMID: 21501486
7.  Association of Uric Acid with Metabolic Syndrome in Men, Premenopausal Women and Postmenopausal Women 
Objective: To explore the relationship between serum uric acid (SUA) and metabolic syndrome (MS) in men, premenopausal women and postmenopausal women. Methods: A cross-sectional study was conducted in 1,834 community-based Southern Chinese participants from June to October 2012. Sex-specific SUA quartiles were used as follows: <345, 345–<400, 400–<468, ≥468 µmol/L in males; and <248, 248–<288, 288–<328, ≥328 µmol/L in females. MS was defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) Criteria. The association between SUA and MS was then analyzed using the STATA software. Results: The odds ratio (OR) for having MS in the highest versus lowest quartiles of SUA levels was 2.46 (95% confidence interval [CI], 1.39 to 4.34, p = 0.002) in men after adjusting for age, sex, history of coronary heart disease, history of stroke, current current smoking, current alcohol use, physical inactivity, education status, and BMI. Further adjusting for above confounders, hypertension and diabetes, the OR for having MS in the highest versus lowest quartiles of SUA was 3.06 (95% CI, 1.64 to 5.70, p < 0.001). The OR for having MS in the highest versus lowest quartiles of SUA was 3.45 (95% CI, 1.38 to 8.64, p = 0.008) and 1.98 (95% CI, 1.16 to 3.37, p = 0.08) in premenopausal women and postmenopausal women after adjusting for age, sex, history of coronary heart disease, history of stroke, current smoking, current alcohol use, physical inactivity, education status, and BMI. Further adjusting for above confounders, hypertension and diabetes, the OR for having MS in the highest versus lowest quartiles of SUA was 3.42 (95% CI, 1.15 to 10.18, p = 0.03) and 1.87 (95% CI, 1.05 to 3.33, p = 0.03) in premenopausal women and postmenopausal women. Conclusions: Higher SUA levels are positively associated with the presence of MS in males and females. Higher SUA levels had a higher risk of having MS in premenopausal women than in postmenopausal women.
PMCID: PMC3987011  PMID: 24619122
uric acid; metabolic syndrome; premenopausal women and postmenopausal women
8.  Maternal carotid remodeling and increased carotid arterial stiffness in normal late-gestational pregnancy as assessed by radio-frequency ultrasound technique 
The adaption of elastic arteries to transient increase in hemodynamic load in normal pregnancy (NP) remains controversial. The purpose of this study was to investigate the NP carotid remodeling and regional arterial stiffness before and after parturition.
Fifty-one NP women and 30 age-matched non-pregnant women were included. All women underwent right common carotid artery (RCCA) measurements with MylabTwice ultrasound instrument (Esaote, Italy). Carotid intima-medial thickness (IMT), pulse wave velocity (PWV, m/s), distensibility coefficient (DC, 1/KPa), α, β, augmentation index (AIx, %) and carotid arterial pressure were obtained by the newly developed ultrasound vascular wall tracking methods: automatic QAS (Quality Arterial Stiffness) and QIMT (Quality Intima-Medial Thickness) Follow up study was performed.
Compared to the non-pregnant controls, the arterial pressures were significantly increased and RCCA diameter was significantly enlarged in late gestational NP women. Twenty months after parturition, carotid diameter, DC, AIx, PWV and arterial wall tension were significantly decreased and had no significant difference with those in non-pregnant controls.
Carotid arterial remodeling and stiffening could be seen in the normal pregnant women, which seems to be a physiological adaption and could be recovered post partum. QIMT and QAS together could provide a comprehensive assessment of the maternal carotid arterial changes during pregnancy.
PMCID: PMC3669620  PMID: 23710816
Arterial stiffness; Intima-media thickness; Carotid artery; Normal pregnancy; Arterial remodeling
9.  Serum Uric Acid Levels and the Risk of Impaired Fasting Glucose: A Prospective Study in Adults of North China 
PLoS ONE  2013;8(12):e84712.
To prospectively investigate the association between serum uric acid (SUA) level and incidence of impaired fasting glucose (IFG) in adult Chinese.
We evaluated 13,328 women and 41,350 men without diabetes and IFG. The participants were classified into quintile according to baseline level of SUA. Data were analyzed to examine the association between SUA levels and the incidence of IFG. We used Cox regression models to estimate the relative risk of IFG after adjusting for known risk factors.
For men, the second quintile of SUA has the lowest cumulative incidence of IFG (29.9%); the fifth quintile of SUA has the highest cumulative incidence of IFG (35.6%). After corrected with Cox regression, the first quartile and the fourth quartile have higher cumulative incidence of IFG than the second quintile, with the HR of 1.11(1.05-1.17) and 1.07(1.01-1.13), respectively. For women, the first quartile of SUA has the lowest cumulative incidence of IFG (20.7%), while the fifth quintile of SUA has the highest cumulative incidence of IFG (30.0%). However, there is no significant difference in IFG between different quintile after adjusted with Cox regression.
The results of this prospective study suggest that there is a higher risk of developing IFG in association with low or high SUA concentrations for men. These relationships were independent of other known risk factors. There is no significant correlation in the risk of developing IFG in association with SUA concentrations for women. Analyses excluding participants with hypertension or with hyperlipidemia and analyses with participants stratified by age reached similar conclusion.
PMCID: PMC3871632  PMID: 24376838
10.  The relationship between serum uric acid and chronic kidney disease among Appalachian adults 
Nephrology Dialysis Transplantation  2010;25(11):3593-3599.
Background. Higher serum uric acid (SUA) levels have been shown to be associated with cardiovascular disease. SUA levels are also associated with hypertension, a strong risk factor for chronic kidney disease (CKD). However, it is unclear whether SUA is independently associated with CKD. We examined the hypothesis that higher SUA levels are positively associated with CKD.
Methods. We analysed data from the C8 Health Study, a population-based study of Appalachian adults aged ≥18 years and free of cardiovascular disease (n = 49,295, 53% women). SUA was examined as gender-specific quartiles. The outcome of interest was CKD (n = 2,980), defined as an estimated glomerular filtration rate of <60 mL/min/1.73 m2 from serum creatinine.
Results. Overall, we observed a clear positive association between increasing quartiles of SUA and CKD, independent of confounders. Compared with the lowest quartile of SUA (referent), the multivariable odds ratios (95% confidence interval) for quartiles 2–4, respectively, of CKD were 1.53 (1.31, 1.78), 2.16 (1.86 2.50) and 4.67 (4.07, 5.36); P-trend < 0.0001. This observed positive association persisted in separate analysis among men (P-trend < 0.0001) and women (P-trend < 0.0001).
Conclusions. In conclusion, higher SUA levels are positively associated with CKD, suggesting that at least part of the reported association between SUA and cardiovascular disease may be mediated by CKD.
PMCID: PMC2980994  PMID: 20501458
Appalachian; chronic kidney disease; creatinine serum; glomerular filtration rate; serum uric acid
11.  Relation between serum uric acid and carotid intima-media thickness in healthy postmenopausal women 
Serum uric acid (SUA) is associated with cardiovascular disease (CVD). However it is still disputed whether the relationship is mediated by other risk factors such as obesity, dyslipidaemia, hypertension and insulin resistance. We explored the association of the uric acid level with carotid intima-media thickness (IMT), a well known marker of CVD, in postmenopausal healthy women.
We consecutively enrolled postmenopausal women undergoing a screening for health evaluation. After an accurate clinical examination, and a biochemical evaluation, the enrolled subjects underwent B mode ultrasonography to assess common carotid intima media thickness.
Among 234 women aged 45–70 years, the uric acid level is associated with carotid IMT independently of other prognostic factors (p=0.03). In particular, women in the highest tertiles of uric acid level have a greater IMT than women in the lowest tertile (p=0.007).
Independently of other cardiovascular risk factors, SUA levels are associated with carotid IMT even in subjects without the metabolic syndrome. This confirms and expands the role of uric acid in the determinism of CVD. Prospective trials would be useful to evaluate interventions aimed at lowering the uric acid level.
PMCID: PMC2780606  PMID: 17551679
Carotid atherosclerosis; Serum uric acid; Postmenopausal women; Cardiovascular disease; Cerebrovascular disease
12.  Clinical Value of Serum Uric Acid in Patients with Suspected Coronary Artery Disease 
Although increased serum uric acid (SUA) concentrations are commonly encountered in patients with risk factors for coronary artery disease (CAD), the clinical value of SUA has not been established.
The study group comprised 687 consecutive patients with suspected CAD who had undergone coronary angiography. CAD was defined as stenosis ≥ 50% of the luminal diameter. CAD severity was expressed as 1-, 2-, or 3-vessel disease. Metabolic syndrome (MS) was defined according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) criteria, and aortofemoral pulse wave velocity (PWV) was obtained by arterial catheterization invasively.
In total, 395 patients had CAD. SUA was higher in patients with CAD as compared to those without CAD (5.5 ± 1.0 vs. 5.2 ± 1.0 mg/dL, p = 0.004). In addition, SUA was significantly associated with the severity of CAD (p = 0.002). However, after adjusting for significant confounding factors including age, diabetes, smoking, cholesterol, MS, and PWV, SUA was not an independent risk factor for CAD (p = 0.151). Based on a subgroup analysis, SUA was more closely associated with CAD in women than in men, and in the highest quartile (≥ 6.4 mg/dL) than in the first quartile (< 4.8 mg/dL); however, these results were not significant (p = 0.062, p = 0.075, respectively). In a multivariate regression analysis, the most important determinant of SUA was MS (i.e., insulin resistance syndrome), which is strongly associated with CAD.
In patients with suspected CAD, SUA was not an independent risk factor for CAD and may be merely a marker of insulin resistance.
PMCID: PMC2829412  PMID: 20195399
Coronary artery disease; Insulin resistance; Uric acid
13.  Large-vessel correlates of cerebral small-vessel disease 
Neurology  2013;80(7):662-669.
Our aim was to investigate the relationship of carotid structure and function with MRI markers of cerebral ischemic small-vessel disease.
The study comprised 1,800 participants (aged 72.5 ± 4.1 years, 59.4% women) from the 3C-Dijon Study, a population-based, prospective cohort study, who had undergone quantitative brain MRI and carotid ultrasound. We used multivariable logistic and linear regression adjusted for age, sex, and vascular risk factors.
Presence of carotid plaque and increasing carotid lumen diameter (but not common carotid artery intima-media thickness) were associated with higher prevalence of lacunar infarcts: odds ratio (OR) = 1.60 (95% confidence interval [CI]: 1.09–2.35), p = 0.02 and OR = 1.24 (95% CI: 1.02–1.50), p = 0.03 (by SD increase). Carotid plaque was also associated with large white matter hyperintensity volume (WMHV) (age-specific top quartile of WMHV distribution): OR = 1.32 (95% CI: 1.04–1.67), p = 0.02, independently of vascular risk factors. Increasing Young elastic modulus and higher circumferential wall stress, reflecting augmented carotid stiffness, were associated with increasing WMHV (effect estimate [β] ± standard error: 0.0003 ± 0.0001, p = 0.024; β ± standard error: 0.005 ± 0.002, p = 0.008). Large WMHV was also associated with increasing Young elastic modulus (OR = 1.22 [95% CI: 1.04–1.42], p = 0.01) and with decreasing distensibility coefficient (OR = 0.83 [95% CI: 0.69–0.99], p = 0.04), independently of vascular risk factors. Associations of carotid lumen diameter with lacunar infarcts and of carotid stiffness markers with WMHV were independent of carotid plaque.
In addition to and independently of carotid plaque, increasing carotid lumen diameter and markers of carotid stiffness were associated with increasing prevalence of lacunar infarcts and increasing WMHV, respectively.
PMCID: PMC3590057  PMID: 23345633
14.  Uric Acid as a Risk Factor for Cardiovascular Disease and Mortality in Overweight/Obese Individuals 
PLoS ONE  2013;8(3):e59121.
The predictive value of serum uric acid (SUA) for adverse cardiovascular events among obese and overweight patients is not known, but potentially important because of the relation between hyperuricaemia and obesity.
The relationship between SUA and risk of cardiovascular adverse outcomes (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality, respectively, was evaluated in a post-hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Participants enrolled in SCOUT were obese or overweight with pre-existing diabetes and/or cardiovascular disease (CVD). Cox models were used to assess the role of SUA as an independent risk factor.
9742 subjects were included in the study; 83.6% had diabetes, and 75.1% had CVD. During an average follow-up time of 4.2 years, 1043 subjects had a primary outcome (myocardial infarction, resuscitated cardiac arrest, stroke, or cardiovascular death), and 816 died. In a univariate Cox model, the highest SUA quartile was associated with an increased risk of cardiovascular adverse outcomes compared with the lowest SUA quartile in women (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.20–2.10). In multivariate analyses, adjusting for known cardiovascular risk factors the increased risk for the highest SUA quartile was no longer statistically significant among women (HR: 0.99; 95% CI: 0.72–1.36) nor was it among men. Analyses of all-cause mortality found an interaction between sex and SUA. In a multivariate Cox model including women only, the highest SUA quartile was associated with an increased risk in all-cause mortality compared to the lowest SUA quartile (HR: 1.51; 95% CI: 1.08–2.12). No relationship was observed in men (HR: 1.06; 95% CI: 0.82–1.36).
SUA was not an independent predictor of cardiovascular disease and death in these high-risk overweight/obese people. However, our results suggested that SUA was an independent predictor of all-cause mortality in women.
PMCID: PMC3606441  PMID: 23533601
15.  Serum uric acid: not a discriminator of coronary heart disease in men and women 
Canadian Medical Association Journal  1973;109(10):986-988.
Fasting serum uric acid (SUA) was measured using a spectrophotometric method in 635 randomized male subjects aged 20 to 70, as part of an epidemiological study carried our among the civil employees of French origin working for the City of Montreal. It was observed that SUA was not age-dependent and that the overall mean value was 6.26 mg./100 ml. On the other hand SUA was studied in 742 males and 260 females, all of whom had had coronarography. A significant difference in SUA between males and females of 1.26 mg./100 ml. was noted. Correlating the SUA levels with the incidence of CHD or the severity of the lesions in the coronary arteries indicated no relationship between CHD and SUA concentrations in men or in women. The results of this study permit the conclusion that SUA is not a discriminator for CHD.
PMCID: PMC1947027  PMID: 4758870
16.  Serum Uric Acid Is More Strongly Associated with Impaired Fasting Glucose in Women than in Men from a Community-Dwelling Population 
PLoS ONE  2013;8(6):e65886.
Serum uric acid (SUA) levels are associated with metabolic syndrome (MetS) and its components such as glucose intolerance and type 2 diabetes. It is unknown whether there are gender-specific differences regarding the relationship between SUA levels, impaired fasting glucose (IFG) and newly detected diabetes. We recruited 1,209 men aged 60±15 (range, 19–89) years and 1,636 women aged 63±12 (range, 19–89) years during their annual health examination from a single community. We investigated the association between SUA levels and six categories according to fasting plasma glucose (FPG) level {normal fasting glucose (NFG), <100 mg/dL; high NFG-WHO, 100 to 109 mg/dL; IFG-WHO, 110 to 125 mg/dL; IFG-ADA, 100 to 125 mg/dL; newly detected diabetes, ≥126 mg/dL; known diabetes} SUA levels were more strongly associated with the different FPG categories in women compared with men. In women, the associations remained significant for IFG-WHO (OR, 1.23, 95% CI, 1.00–1.50) and newly detected diabetes (OR, 1.33, 95% CI, 1.03–1.72) following multivariate adjustment. However, in men all the associations were not significant. Thus, there was a significant interaction between gender and SUA level for newly detected diabetes (P = 0.005). SUA levels are associated with different categories of impaired fasting glucose in participants from community-dwelling persons, particularly in women.
PMCID: PMC3681777  PMID: 23785457
17.  The Relationship between Serum Uric Acid and Spirometric Values in Participants in a Health Check: The Takahata Study 
Background: Tissue hypoxia induces the degradation of adenosine triphosphate, resulting in the production of uric acid (UA). Patients with chronic obstructive pulmonary disease (COPD) have been reported to have high serum levels of UA (sUA), compared with control subjects. However, the relationship between sUA levels and spirometric measures has not been investigated in detail in a general population.
Methods: Subjects aged 40 years or older (n = 2,917), who had participated in a community-based annual health check in Takahata, Japan, in 2004 and 2005, were enrolled in the study. These subjects performed spirometry, their blood pressure was measured, and a blood sample was taken.
Results: sUA levels were significantly higher in males than in females. Percent predicted forced vital capacity [FVC %predicted] (r = -0.13) and forced expiratory volume in 1 s [FEV1 %predicted] (r = -0.118) were inversely correlated with sUA levels in females but not in males. Univariate regression analysis indicated that age, body mass index (BMI), ethanol intake, mean blood pressure (BP), and serum creatinine (sCr) were significantly associated with sUA levels in males. In females, age, BMI, mean BP, hemoglobin A1c, sCr, FVC %predicted, and FEV1 %predicted were significantly associated with sUA levels. Multiple linear regression analysis showed that for both genders, FVC %predicted and FEV1 %predicted were predictive for sUA levels, independently of the other clinical parameters. Subjects with lung restriction had higher sUA levels than subjects without lung restriction. In addition, subjects with moderate and severe airflow limitation had higher sUA levels than subjects without airflow limitation or those with mild airflow limitation.
Conclusion: FVC %predicted and FEV1 %predicted were significantly associated with sUA levels in a general population.
PMCID: PMC3156995  PMID: 21850198
uric acid; spirometry; pulmonary function; epidemiology
18.  Association of Serum Uric Acid with Incident Atrial Fibrillation (From the Atherosclerosis Risk in Communities [ARIC] Study) 
The American Journal of Cardiology  2011;108(9):1272-1276.
Atrial fibrillation (AF) is one of the most common arrhythmias seen in clinical practice. Current evidence suggests that serum uric acid (SUA) could be a marker of oxidative damage a factor reported as part of the mechanisms of AF. The purpose of this study was to evaluate if SUA predicted AF in the Atherosclerosis Risk in Communities study (ARIC). This analysis included 15,382 AF-free black and white men and women, aged 45-64, from the ARIC study, a population-based prospective cohort in the US. SUA was determined using the uricase-peroxidase method at baseline. The primary outcome was the incidence of AF defined as the occurrence of AF detected from hospital discharge codes, scheduled study electrocardiograms (ECG) and /or death certificates during follow-up period (1987-2004). We identified 1085 cases of incident AF. In Cox proportional hazards models adjusted for age, sex, race, center, education, body-mass index, serum glucose, systolic and diastolic blood pressure, LDL cholesterol, alcohol use, prevalent coronary heart disease and heart failure, serum creatinine, use of diuretics, and p wave duration on the ECG (as a measure of left atrial size) at baseline, the hazard ratio (HR) of AF associated with a 1-standard deviation increment in SUA was 1.16; 95% CI 1.06 -1.26. The association of SUA with AF risk differed by race and gender (p for interaction<0.01). In conclusion, elevated SUA is associated with a higher risk of AF, particularly among blacks and women. Further studies should replicate this association and explore potential mechanisms.
PMCID: PMC3404126  PMID: 21855838
Atrial fibrillation; Uric acid; Epidemiology
19.  Association of Serum Uric Acid with 2-Hour Postload Glucose in Chinese with Impaired Fasting Plasma Glucose and/or HbA1c 
PLoS ONE  2013;8(7):e67759.
To examine whether serum uric acid (SUA) is associated with 2-hour postload glucose (2-h PG) in Chinese with impaired fasting plasma glucose (IFG) and/or HbA1c (IA1C).
Research Design and Methods
Anthropometric and biochemical examinations, such as SUA concentration, were performed in 3763 individuals from all the villages in Baqiao County, China. A 75-g oral glucose tolerance test (OGTT) was conducted in 1197 Chinese with prediabetes as having IFG (110≤ fasting plasma glucose [FPG] <126 mg/dl and HbA1c <6.5%), IA1C (5.7% ≤ HbA1c <6.5% and FPG <126 mg/dl), or both.
The present study included 1197 participants with IFG and/or IA1C (mean age 56.5±10.3 years; 50.6% men). In multivariate linear regression, after adjustment for gender, age, smoking and drinking, body mass index (BMI), systolic and diastolic blood pressure (SBP, DBP), lipid profiles, logarithmic transformed C-reactive protein (log-CRP), estimated glomerular filtration rate (e-GFR), FPG and HbA1c, with a 1-mg/dl increment of SUA, 2-h PG increased by 5.04±0.72 (P<0.001), 3.06±1.08 (P = 0.001), 5.40±1.26 (P<0.001), and 2.34±2.16 mg/dl (P = 0.056) in all participants, in participants with normal glucose tolerance (NGT), with impaired glucose tolerance (IGT), and with 2-h newly diagnosed diabetes (2-h NDM, with 2-h PG ≥200 mg/dl), respectively. In both men and women, 2-h PG increased progressively and significantly from the lower to the upper SUA tertiles (P<0.001). Moreover, in multivariate logistic regression, 1-standard deviation (SD; 1.53 mg/dl) increment of SUA was significantly associated with a 36% higher risk for 2-h NDM (Odds ratio [CI 95%]: 1.36 [1.09–1.99]; P = 0.03).
SUA is significantly associated with 2-h PG in Chinese with IFG and/or IA1C.
PMCID: PMC3700996  PMID: 23844086
20.  Human common carotid wall shear stress as a function of age and gender: a 12-year follow-up study 
Age  2011;34(6):1553-1562.
Hemodynamic forces play a role in the development of atherosclerosis. Their variations with age have been assessed in cross-sectional, but not longitudinal, studies. The aim of the present study was to investigate in both sexes the age-dependent change in wall shear stress and arterial stiffness in subjects studied twice 12 years apart. Forty-eight subjects (15 women and 33 men) were studied twice 12 years apart. Subjects underwent blood viscosity measurement and echo-Doppler of carotid arteries, from which the intima–media thickness (IMT) was measured and the wall shear stress and Peterson’s elastic modulus were calculated. Blood viscosity increased in both sexes, more markedly in women (+13.2%) than men (+7.2%). Common carotid diameter increased in both sexes, but in men (+7.4%) more than in women (+5.5%). Peak and mean velocity decreased at follow-up by 10.7% and 18.9% in women and by 14.2% and 18.1% in men. Peak and mean shear stress significantly decreased in men by 13.0% and 17.5%, respectively, while in women only the mean shear stress was reduced (−11.8%). The IMT of the common carotid artery increased by 29% in women and 20% in men. Arterial stiffness significantly increased (+74.5% in women and +28.0% in men). The percent change in mean shear stress was significantly and inversely associated with the percent change in IMT. The data of this study show that, in a middle-aged population observed for almost 12 years, the mean shear stress decreases significantly in both sexes, while peak shear stress decreases significantly only in men. The change in mean shear stress is inversely associated with changes in IMT. Arterial stiffness, on the other hand, increases with aging.
PMCID: PMC3528365  PMID: 21989971
Wall shear stress; Carotid artery; Arterial stiffness
21.  Serum Uric Acid and Non-Alcoholic Fatty Liver Disease in Non-Diabetic Chinese Men 
PLoS ONE  2013;8(7):e67152.
Increased serum uric acid (SUA) levels may be involved in the development of non-alcoholic fatty liver disease (NAFLD) in men presenting with metabolic syndrome (MetS) and/or insulin resistance. We aimed to determine the independent relationship between SUA and NAFLD in non-diabetic Chinese male population, and to explore the determinants of SUA levels among indexes of adiposity, lipid, and genotypes pertaining to triglycerides metabolism, inflammation, oxidative stress, and SUA concentrations. A total of 1440 men, classified depending on the presence of ultrasonographically detected NAFLD, underwent a complete healthy checkup program. Genotypes were extracted from our previously established genome-wide association study database. After adjusting for age, smoking, drinking, body mass index, homeostasis model assessment of insulin resistance, C-reactive protein, creatinine, alanine aminotransferase (ALT) and components of metabolic syndrome, the odds ratio for NAFLD, comparing the highest with the lowest SUA quartile, was 2.81 (95% confidence interval 1.66–4.76). A stepwise multivariate linear regression analysis (R2 = 0.238, P<0.001) retained age, waist circumference, serum creatinine, triglycerides, the Q141K variant in ABCG2 (rs2231142) and NAFLD as significant predictors of SUA levels (all P<0.001). Besides, ALT and Met196Arg variant in TNFRSF1B (rs1061622) additionally associated with SUA among individuls with NAFLD. Our data suggest that in Chinese men, elevated SUA is significantly associated with NAFLD, independent of insulin resistance and other metabolic disorders, such as central obesity or hypertriglyceridemia. Meanwhile, among subjects with NAFLD, index of liver damage, such as elevated ALT combined with genetic susceptibility to inflammation associated with increased SUA levels.
PMCID: PMC3720733  PMID: 23935829
22.  Serum uric acid levels are associated with hypertension and metabolic syndrome but not atherosclerosis in Chinese inpatients with type 2 diabetes 
Journal of Hypertension  2015;33(3):482-490.
Serum uric acid (SUA) is associated with many cardiovascular risk factors such as hypertension (HTN) and metabolic syndrome (MetS). However, the association of SUA with atherosclerosis remains controversial. Our aim was to investigate the relationships of SUA with HTN, MetS and atherosclerosis in Chinese inpatients with type 2 diabetes.
This cross-sectional study was performed with a sample of 2388 hospitalized Chinese patients with type 2 diabetes. Both carotid and lower limb atherosclerotic lesions were assessed for intima–media thickness, plaque and stenosis by Doppler ultrasound. Atherosclerotic plaque and stenosis were defined as the presence of either carotid or lower limb plaques and stenoses, respectively.
There were significant increases in the prevalence of both HTN and MetS across the SUA quartiles (HTN: 43.4, 49.6, 56.1 and 66.3% for the first, second, third and fourth quartiles, respectively, P < 0.001; MetS: 59.9, 68.8, 74.7 and 84.9% for the first, second, third and fourth quartiles, respectively, P < 0.001). A fully adjusted multiple logistic regression analysis revealed that SUA quartile was independently associated with the presence of HTN (P = 0.001) and MetS (P = 0.006). The prevalence of atherosclerotic plaque and stenosis was obviously higher in the patients with either HTN or MetS than in those without HTN or MetS. However, there was no significant association of SUA quartile with the presence of atherosclerotic lesions.
SUA levels were closely associated with HTN and MetS, but not with atherosclerosis in type 2 diabetes. Our findings strongly suggest that, in select populations such as those with type 2 diabetes, the role of uric acid in atherosclerosis might be attributable to other cardiovascular risk factors, such as HTN and MetS.
PMCID: PMC4309490  PMID: 25405332
atherosclerosis; hypertension; hyperuricemia; metabolic syndrome; type 2 diabetes; uric acid
23.  Associations of Serum Uric Acid and SLC2A9 Variant with Depressive and Anxiety Disorders: A Population-Based Study 
PLoS ONE  2013;8(10):e76336.
Limited information exists regarding the association between serum uric acid (SUA) and psychiatric disorders. We explored the relationship between SUA and subtypes of major depressive disorder (MDD) and specific anxiety disorders. Additionally, we examined the association of SLC2A9 rs6855911 variant with anxiety disorders.
We conducted a cross-sectional analysis on 3,716 individuals aged 35–66 years previously selected for the population-based CoLaus survey and who agreed to undergo further psychiatric evaluation. SUA was measured using uricase-PAP method. The French translation of the semi-structured Diagnostic Interview for Genetic Studies was used to establish lifetime and current diagnoses of depression and anxiety disorders according to the DSM-IV criteria.
Men reported significantly higher levels of SUA compared to women (357±74 µmol/L vs. 263±64 µmol/L). The prevalence of lifetime and current MDD was 44% and 18% respectively while the corresponding estimates for any anxiety disorders were 18% and 10% respectively. A quadratic hockey-stick shaped curve explained the relationship between SUA and social phobia better than a linear trend. However, with regards to the other specific anxiety disorders and other subtypes of MDD, there was no consistent pattern of association. Further analyses using SLC2A9 rs6855911 variant, known to be strongly associated with SUA, supported the quadratic relationship observed between SUA phenotype and social phobia.
A quadratic relationship between SUA and social phobia was observed consistent with a protective effect of moderately elevated SUA on social phobia, which disappears at higher concentrations. Further studies are needed to confirm our observations.
PMCID: PMC3812204  PMID: 24204615
24.  Relationships between high-sensitive C-reactive protein and markers of arterial stiffness in hypertensive patients. Differences by sex 
The present study was designed to evaluate the relationship between high-sensitivity C-reactive protein (hs-CRP) and arterial stiffness according to sex in patients with arterial hypertension.
A case-series study was carried out in 258 hypertensive patients without antecedents of cardiovascular disease or diabetes mellitus. Nephelometry was used to determine hs-CRP. Office or clinical and home blood pressures were measured with a validated OMRON model M10 sphygmomanometer. Ambulatory blood pressure monitoring was performed with the SpaceLabs 90207 system. Pulse wave velocity (PWV) and central and peripheral augmentation index (AIx) were measured with the SphygmoCor system, and a Sonosite Micromax ultrasound unit was used for automatic measurements of carotid intima-media thickness (IMT). Ambulatory arterial stiffness index and home arterial stiffness index were calculated as “1-slope” from the within-person regression analysis of diastolic-on-systolic ambulatory blood pressure.
Central and peripheral AIx were greater in women than in men: 35.31 ± 9.95 vs 26.59 ± 11.45 and 102.06 ± 20.47 vs 85.97 ± 19.13, respectively. IMT was greater in men (0.73 ± 0.13 vs 0.69 ± 0.10). hs-CRP was positively correlated to IMT (r = 0.261), maximum (r = 0.290) and to peripheral AIx (r = 0.166) in men, and to PWV in both men (r = 0.280) and women (r = 0.250). In women, hs-CRP was negatively correlated to central AIx (r = −0.222). For each unit increase in hs-CRP, carotid IMT would increase 0.05 mm in men, and PWV would increase 0.07 m/sec in men and 0.08 m/sec in women, while central AIx would decrease 2.5 units in women. In the multiple linear regression analysis, hs-CRP explained 10.2% and 6.7% of PWV variability in women and men, respectively, 8.4% of carotid IMT variability in men, and 4.9% of central AIx variability in women.
After adjusting for age, other cardiovascular risk factors and the use of antihypertensive and lipid-lowering drugs, hs-CRP was seen to be positively correlated to carotid IMT in men, and negatively correlated to central AIx in women. The association of hs-CRP to arterial stiffness parameters differs between men and women.
PMCID: PMC3473264  PMID: 22676422
Hypertension; High-sensitive C-reactive protein; Arterial stiffness
25.  Effects of menopause and hormone replacement therapy on the associations of hyperuricemia with mortality 
Atherosclerosis  2012;226(1):220-227.
Serum uric acid (SUA) levels have been associated with cardiovascular and all-cause mortality. It remains unclear whether these associations differ by gender, menopausal status and hormone replacement therapy (HRT) and whether they persist after adjustment for known cardiovascular risk factors.
We determined the associations between fasting SUA level and death certificate-based mortality among 5856 participants of the third US National Health and Nutrition Examination Survey aged ≥20 years recruited between 1988–1994 and followed for mortality until December 2006 (mean follow-up: 13.5 years; maximum follow-up: 18 years). Cox proportional hazards regression analysis was used to adjust for demographic characteristics, cardiovascular risk factors and other variables potentially associated with SUA levels.
Among women, SUA level was associated with all-cause and cardiovascular mortality (adjusted hazard ratio [AHR] 1.17, 95% CI 1.03–1.32 and AHR 1.23 (1.01–1.51) respectively per unit increase in SUA. These associations persisted among postmenopausal but not premenopausal women. Furthermore, among postmenopausal women, significant associations were identified between SUA and all-cause (AHR 1.30 [1.11–1.51]) or cardiovascular (AHR 1.61 [1.33–1.94]) mortality only among women not taking HRT, but not among women on HRT.
We did not identify associations between SUA levels and all-cause or cardiovascular mortality in men, either under or over 51 years of age, in unadjusted or adjusted analyses.
SUA level predicts cardiovascular and all-cause mortality independently of major predictors and risk factors in postmenopausal women not taking HRT but not in premenopausal women, postmenopausal women on HRT, or men.
PMCID: PMC4240945  PMID: 23141471
serum uric acid; mortality; cardiovascular mortality; cohort study; population-based

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