Elevated serum uric acid (UA) is associated with cardiovascular disease (CVD) but its association with coronary artery calcium (CAC) is inconsistent. This study examined ethnic differences in the association of UA levels with CAC severity and progression. Participants included 202 white and 166 Filipino postmenopausal women without known CVD. White women originated from the Rancho Bernardo cohort study, whereas Filipino women were convenience sampled from comparable localities. Baseline UA levels and CVD risk factors were measured in 1995 to 1999. CAC was assessed by electron beam computed tomography (EBCT) in 2000 to 2002 (EBCT1) and repeated in 2005 to 2007 (EBCT2). EBCT1 CAC density scores were categorized by severity: minimal 0 to 10, mild 11 to 100, moderate 101 to 399, and severe ≥400. Progression was defined as CAC volume score increases of ≥2.5 mm 3 between scans. White women were older at baseline than Filipinas (64.6 vs 59.3 years, p <0.001). Filipinas had increased UA levels (235.8 vs 294.2 μmol/L, p <0.001), diabetes (35.5% vs 5.2%, p <0.001), hypertension (69.6% vs 45.2%, p <0.001), and statin use (32.8% vs 18.7%, p = 0.002). CAC severity did not vary by ethnicity (p = 0.502), but Filipinas experienced more CAC progression than whites (53.0% vs 39.1%, p = 0.016). Adjustment for CVD risk factors identified a positive association between UA levels and increasing CAC severity at EBCT1 in Filipinas (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.05 to 1.71) but not whites (OR 0.94, 95% CI 0.71 to 1.25). Higher UA levels predicted CAC progression in both cohorts (OR 1.26, 95% CI 1.02 to1.56). In conclusion, these results support use of UA as an ethnicity-specific marker of CAC severity and as a marker of CAC progression among postmenopausal women.
Coronary heart disease and related events are the leading cause of death and disability among women in the United States but few studies examine differences in burden and risk among different ethnic groups, and Filipino women are particularly underrepresented. Evidence suggests that serum uric acid (UA) may be a stronger marker for coronary artery calcium (CAC) in Filipina-Americans than white women. Healey et al reported that Filipinos are genetically predisposed for higher UA levels because of reduced kidney function. Additionally, Filipino immigrants in the United States have higher rates of gout, a disease characterized by elevated UA, compared with Filipinos in the Philippines, attributable to cultural and environmental changes. Postmenopausal Filipino women also have greater prevalences of type 2 diabetes mellitus and other metabolic syndrome components than white women of similar age, body size, and percent body fat suggesting ethnic differences in chronic disease risk profiles. This study characterizes and compares the association of CAC severity and CAC progression by baseline UA levels between community-dwelling postmenopausal white and Filipino women.
Methods
A convenience sample of 453 Filipino women aged ≥40 years was recruited from 1995 to 1999 in San Diego to participate in a study of chronic conditions including cardiovascular disease (CVD), hypertension (HTN), type 2 diabetes mellitus, and osteoporosis. Non-Hispanic, white, University of California San Diego–Rancho Bernardo Study participants with UA measurement from 1992 to 1996 or 1996 to 1999 were used as a comparator group. Standardized questionnaires were used to collect information on demographic characteristics, age at menopause, behaviors including cigarette smoking (never, past, or present), alcohol use (≥3 drinks/week), physical activity (≥3 times/week), and medical history. Baseline clinical measurements for systolic and diastolic blood pressures, oral glucose tolerance test, body mass index, fasting plasma glucose, medication use, cholesterol (low-density lipoprotein, high-density lipoprotein, and total), and triglycerides were evaluated at the same clinic and with the same protocols and staff for both groups.
In 2000 to 2002, postmenopausal white and Filipino women aged 55 to 80 years who were without known CVD (defined as a history of myocardial infarction, angina pectoris by physician diagnosis or clinical ascertainment at the baseline visit, or coronary artery revascularization) were invited for an electron beam computed tomography (EBCT) scan to assess CAC levels and visceral and subcutaneous adiposity (EBCT1). In 2005 to 2007, surviving participants still residing in San Diego who remained CVD free were invited to attend a second EBCT scan (EBCT2). Details of the EBCT scan visits have been previously reported. Total CAC scores were quantified by the Agatston method. CAC severity was categorized based on the Rumberger method as minimal 0 to 10, mild 11 to 100, moderate 101 to 399, and severe ≥400. CAC progression was defined using the Hokanson method with the formula
where values ≥2.5 mm 3 indicate progression.
HTN was defined as systolic blood pressure >140 mm Hg, diastolic blood pressure >90 mm Hg, treatment with antihypertensive medication, or by physician diagnosis. Type 2 diabetes mellitus was defined as fasting plasma glucose ≥6.993 mmol/L (126 mg/dl), 2-hour postchallenge glucose ≥11.1 mmol/L (200 mg/dl), physician diagnosis, or treatment with an oral hypoglycemic agent or insulin. Estimated glomerular filtration rate was calculated using serum creatinine by the Modification of Diet in Renal Disease study group equation and categorized into stages of kidney damage based on National Kidney Foundation guidelines: normal ≥90 ml/min, mild decrease 60 to 89 ml/min, moderate decrease 30 to 59 ml/min, severe decrease 15 to 29 ml/min, and kidney failure <15 ml/min.
Crude analysis of covariates and outcomes by ethnic group was performed using chi-square tests for categorical variables and t tests for continuous variables. Age-adjusted means and proportions by ethnic group were calculated using analysis of covariance and binary logistic regression, respectively. Multivariate ordinal logistic regression models were used to assess the relation between a 1-unit increase in serum UA levels (in mg/dl or 59.48 μmol/L) and odds for a higher CAC severity category versus the cumulative odds of all categories below it. Multivariate logistic regression was similarly used to assess a 1-unit increase in UA levels and odds for CAC progression.
Four models examined associations of UA levels with CAC severity and progression after adjusting for age at EBCT visit and follow-up time (model 1); for model 1 covariates plus diabetes and HTN (model 2); for model 1 and 2 covariates plus statin use and visceral adiposity (model 3); for model 1, 2, and 3 covariates plus estrogen use (model 4). CAC severity models used age, statin use, and visceral adiposity measured at EBCT1 and time from baseline to EBCT1. CAC progression models used age, statin use, and visceral adiposity measured at EBCT2 and time from EBCT1 to EBCT2. Covariates were selected based on known associations in the literature and when statistical associations were found with p <0.10. Multiplicative interactions between ethnic group and UA levels were evaluated with p <0.10. Akaike’s Information Criterion values were used to determine the best-fit model between similar variables. All ordinal logistic regression models met the proportional odds assumption assessed with the Brant test at a p value of ≤0.10. Data were analyzed with Stata/MP, version 11.0 (StataCorp LP, College Station, Texas) and SAS, version 9.1.3 (SAS Institute, Cary, North Carolina).
Results
Three hundred sixty-eight women attended the EBCT1 visit and had UA levels measured at baseline. Of these, 302 women attended the follow-up EBCT visit an average of 4.6 years later. Table 1 lists age-adjusted characteristics in white and Filipino women. At baseline, white women were older and had higher rates of smoking, alcohol consumption, and estrogen use than Filipino women. White women also had lower UA levels, poorer kidney function, lower low-density lipoprotein cholesterol and triglyceride values, higher high-density lipoprotein cholesterol values, lower fasting and postchallenge glucose, and lower rates of HTN and diabetes than Filipino women. Body mass index and exercise did not differ by ethnicity, although visceral adiposity was significantly lower in white than Filipino women at EBCT1. The mean time interval between baseline and EBCT1 was longer for white than Filipino women, but there were no differences in the length of time between EBCT visits. At both EBCT visits, more Filipino than white women were using statins.
| Variable | Full Sample | White | Filipina | p Value |
|---|---|---|---|---|
| Baseline visit | n = 368 | n = 202 | n = 166 | |
| Age (yrs) | 62.2 (6.4) | 64.6 (5.5) | 59.3 (6.2) | <0.001 |
| Ever smoker (%) | 33.7 | 49.8 | 14.0 | <0.001 |
| Exercise ≥3×/week (%) | 72.0 | 69.9 | 75.0 | 0.322 |
| Alcohol consumption ≥3×/week (%) | 26.1 | 44.7 | 1.3 | <0.001 |
| Estrogen usage (%) | 44.6 | 66.4 | 19.0 | <0.001 |
| HTN (%) | 56.3 | 45.2 | 69.6 | <0.001 |
| Type 2 diabetes (%) | 18.5 | 5.2 | 35.5 | <0.001 |
| Glomerular filtration rate (ml/min) † | 75.0 (18.3) | 68.7 (13.5) | 82.4 (20.4) | <0.001 |
| Body mass index (kg/m 2 ) | 25.9 (4.2) | 26.1 (4.4) | 25.6 (4.4) | 0.275 |
| LDL cholesterol (mmol/L) † | 3.33 (0.85) | 3.23 (0.89) | 3.45 (0.90) | 0.028 |
| HDL cholesterol (mmol/L) | 1.57 (0.41) | 1.71 (0.40) | 1.40 (0.41) | <0.001 |
| Triglycerides (mmol/L) | 1.61 (0.88) | 1.49 (0.91) | 1.76 (0.91) | 0.008 |
| Fasting plasma glucose (mmol/L) | 5.77 (1.60) | 5.54 (1.66) | 6.04 (1.67) | 0.006 |
| Postchallenge glucose (mmol/L) † | 8.55 (4.16) | 9.64 (3.97) | 10.58 (4.01) | <0.001 |
| Serum UA (μmol/L) | 262.2 (78.5) | 235.8 (77.5) | 294.2 (78.2) | <0.001 |
| EBCT1 visit (2000–2002) | n = 368 | n = 202 | n = 166 | |
| Age (yrs) | 65.6 (6.1) | 66.6 (6.1) | 64.4 (6.0) | <0.001 |
| Follow-up time from baseline (yrs) | 5.8 (1.2) | 6.3 (1.1) | 5.1 (0.8) | <0.001 |
| Statin use (%) | 25.0 | 18.7 | 32.8 | 0.002 |
| Visceral adiposity (cm 3 ) † | 65.8 (32.4) | 62.4 (32.5) | 69.8 (32.5) | 0.032 |
| Subcutaneous adiposity (cm 3 ) † | 157.7 (65.0) | 158.5 (65.6) | 156.8 (65.7) | 0.811 |
| EBCT2 visit (2005–2007) | n = 301 | n = 169 | n = 132 | |
| Age (yrs) | 70.4 (6.0) | 71.2 (5.8) | 69.4 (6.1) | 0.011 |
| Follow-up time from EBCT1 (yrs) | 4.6 (0.3) | 4.6 (0.4) | 4.7 (0.3) | 0.562 |
| Statin use (%) | 43.4 | 33.4 | 55.8 | <0.001 |
| Visceral adiposity (cm 3 ) | 75.6 (38.2) | 73.0 (38.3) | 78.9 (38.4) | 0.189 |
| Subcutaneous adiposity (cm 3 ) | 150.0 (60.7) | 147.4 (60.4) | 152.1 (60.5) | 0.511 |
∗ Variables assessed at baseline are adjusted for age at baseline. Variables assessed at EBCT1 are adjusted for age at EBCT1. Variables assessed at EBCT2 are adjusted for age at EBCT2.
† Seven white women were excluded because of missing values.
As listed in Table 2 , the significant elevation in age-adjusted UA levels in Filipinas compared with white women persisted across categories of HTN and kidney dysfunction. UA levels were also significantly higher in Filipino than white women at every level of CAC severity and in those with and without CAC progression.
| Variable | Full Sample | White | Filipina | p Value | |||
|---|---|---|---|---|---|---|---|
| n | Mean ± SD | n | Mean ± SD | n | Mean ± SD | ||
| HTN | |||||||
| No HTN | 161 | 245.5 ± 77.4 | 104 | 223.3 ± 70.2 | 57 | 286.0 ± 71.7 | <0.001 |
| HTN | 207 | 275.2 ± 77.4 | 98 | 251.3 ± 82.9 | 109 | 296.6 ± 82.3 | <0.001 |
| Renal function | |||||||
| Normal | 65 | 253.5 ± 81.5 | 14 | 191.6 ± 74.5 | 51 | 276.2 ± 72.2 | <0.001 |
| Mild decrease | 220 | 253.9 ± 77.1 | 122 | 230.3 ± 66.1 | 98 | 283.5 ± 66.4 | <0.001 |
| Moderate decrease | 75 | 298.5 ± 81.4 | 58 | 272.0 ± 90.0 | 17 | 370.6 ± 95.0 | <0.001 |
| CAC severity at EBCT1 | |||||||
| Minimal | 179 | 250.3 ± 78.7 | 105 | 232.9 ± 68.3 | 74 | 272.7 ± 68.8 | <0.001 |
| Mild | 84 | 277.7 ± 77.3 | 42 | 248.9 ± 75.2 | 42 | 307.4 ± 75.2 | <0.001 |
| Moderate | 71 | 257.1 ± 77.9 | 36 | 240.0 ± 88.3 | 35 | 276.9 ± 88.5 | 0.113 |
| Severe | 34 | 296.9 ± 78.1 | 19 | 260.2 ± 83.0 | 15 | 347.3 ± 83.4 | <0.001 |
| CAC progression | |||||||
| No progression | 165 | 244.1 ± 76.4 | 102 | 223.2 ± 68.2 | 62 | 275.8 ± 68.4 | <0.001 |
| Progression | 137 | 271.7 ± 76.5 | 67 | 244.5 ± 76.3 | 70 | 300.2 ± 76.3 | <0.001 |
∗ Serum UA values (in μmol/L) by HTN and renal dysfunction categories are adjusted for age at baseline. Serum UA values by CAC severity category are adjusted for age at EBCT1. Serum UA values by CAC progression are adjusted for age at EBCT2. Conversion factor to US customary units: UA ×0.0168 to mg/dl.
Figure 1 displays a comparison of the proportional distributions of the outcome categories by ethnic group. At EBCT1, there were no statistical differences in CAC severity by ethnicity. However, a greater proportion of Filipino women than white women experienced CAC progression over approximately the next 5 years.
Associations of UA levels with CAC severity and CAC progression are listed in Table 3 . Crude assessment of interactions between ethnic group and the UA level for each outcome was not statistically significant. There were no significant associations between UA levels and CAC severity in analyses for all women combined. However, after stratification by ethnicity, the UA level was associated with a 33% to 37% increased adjusted odds of higher CAC severity in Filipino women but not white women. For all women combined, the UA level was associated with significantly increased odds of CAC progression. Across all models, the odds of progression were similar, although not statistically significant, after stratification by ethnicity.
