Serum Urate and Incident Cardiovascular Disease: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

<div><p>Objective</p><p>There is controversy about whether serum urate (sUA) predicts future cardiovascular disease (CVD) independently of classical risk factors, and the age at which any prediction starts. We studied the sUA-CVD association among generally healthy adults.</p><p>Methods</p><p>CARDIA recruited 5115 black and white individuals aged 18–30 years in 1985–1986 (year-0). Fatal and nonfatal CVD events by year 27 (n = 164) were ascertained during annual contacts and classified using medical records. The association with sUA (year-0, 10, 15 and 20) was modeled using Cox proportional hazards regression, pooling over gender-specific quartiles.</p><p>Results</p><p>Mean sUA concentration was higher in men than women, but increased over time in both genders. Those with elevated sUA had worse metabolic profiles that substantially deteriorated over time. Adjusting for demographic and lifestyle factors (the minimal model), baseline sUA concentration was positively associated with incident CVD (hazard ratio (HR) per mg/dL = 1.21; 95% confidence interval: 1.05, 1.39; P = 0.005). This positive association attenuated to nonsignificance in the full model accounting simultaneously for classical CVD risk factors (HR = 1.09; 0.94, 1.27; P = 0.24). Both the minimal and full models appeared to show stronger associations (than year-0 sUA) between year-10 sUA and incident CVD (HR = 1.27 and 1.12, respectively), but sUA was not statistically significant in the full model. Despite fewer events, year-15 sUA showed a significant sUA-CVD association pattern, with minimal model association magnitude comparable to year-10, and remained significant in the full model (HR = 1.19; 1.02, 1.40; P = 0.03). Hyperuricemia at year-15 strongly predicted CVD risk (HR = 2.11; 1.34, 3.33; P = 0.001), with some attenuation in the full model (HR = 1.68; P = 0.04).</p><p>Conclusions</p><p>sUA may be an early biomarker for CVD in adults entering middle age. The prediction of CVD by sUA appeared to strengthen with aging. The potential complex relation of sUA with deterioration of a cluster of metabolic abnormalities warrants future exploration.</p></div

Unadjusted participant characteristics (mean±SD or percent) of participants across exam years.

<p>^a Prevalent CVD endpoints and missing data on sUA or covariates at the year of sUA measurement were excluded from the analyses.</p><p>^b HOMA-IR was calculated as (glucose × insulin) / 405 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0138067#pone.0138067.ref023" target="_blank">23</a>].</p><p>Unadjusted participant characteristics (mean±SD or percent) of participants across exam years.</p

Longitudinal association between sUA and the incidence of any fatal or nonfatal CVD endpoints by year 27.

<p>sUA, serum urate; CVD, cardiovascular disease; Y, year; Q, quartile; BMI, body mass index; CI, confidence interval.</p><p>^a Model 1: adjusted for year 0 age, sex, race, clinic, education level, smoking status, physical activity and intakes of total calories, alcohol and protein.</p><p>^b Model 1 + year 0 BMI, systolic and diastolic blood pressure, anti-hypertension medication use (excluding those taking diuretics), diuretics use, and glomerular filtration rate.</p><p>^c Model 2: adjusted for age, sex, race, clinic, education level, smoking status and physical activity at year 10, and average intakes of total calories, alcohol and protein at years 0 and 7.</p><p>^d Model 2 + year 10 BMI, systolic and diastolic blood pressure, anti-hypertension medication use (excluding those taking diuretics), diuretics use, and glomerular filtration rate.</p><p>^e Model 3: adjusted for age, sex, race, clinic, education level, smoking status and physical activity at year 15, and average intakes of total calories, alcohol and protein at years 0 and 7.</p><p>^f Model 3 + year 15 BMI, systolic and diastolic blood pressure, anti-hypertension medication use (excluding those taking diuretics), diuretics use, and glomerular filtration rate</p><p>^g Hazard ratio (95% CI) for the incidence of any fatal or nonfatal CVD endpoints by the end of 2012 (year 25) across sUA tertiles, reference group is participants in the lowest tertile of sUA concentrations.</p><p>^h Hazard ratio (95% CI) for the incidence of any fatal or nonfatal CVD endpoints per mg/dL sUA when using continuous sUA variable.</p><p>ⁱ<i>P</i>-values for the association between sUA and CVD when using continuous sUA variables.</p><p>^j Values are presented as “hyperuricemia group (reference group)”. Numbers in the reference group (participants without hyperuricaemia, i.e. sUA <6.8 mg/dL) are given in parentheses.</p><p>^kHazard ratio (95% CI) for the incidence of any fatal or nonfatal CVD endpoints by the end of 2012 (year 25) for the hyperuricemia group.</p><p>Longitudinal association between sUA and the incidence of any fatal or nonfatal CVD endpoints by year 27.</p