Associations between serum uric acid and markers of subclinical atherosclerosis in young adults. The cardiovascular risk in Young Finns study

Abstract

Background and methods

Serum uric acid (SUA) is a suggested biomarker for established coronary artery disease, but the role of SUA in early phases of atherosclerosis is controversial. The relations of SUA with vascular markers of subclinical atherosclerosis, including carotid artery intima-media thickness (cIMT), carotid plaque, carotid distensibility (Cdist) and brachial flow-mediated dilatation (FMD) were examined in 1985 young adults aged 30–45 years. In addition to ordinary regression, we used Mendelian randomization techniques to infer causal associations.

Results

In women, the independent multivariate correlates of SUA included BMI, creatinine, alcohol use, triglycerides, glucose and adiponectin (inverse association) (Model R² = 0.30). In men, the correlates were BMI, creatinine, triglycerides, C-reactive protein, alcohol use, total cholesterol and adiponectin (inverse) (Model R² = 0.33). BMI alone explained most of the variation of SUA levels both in women and men (Partial R² ∼ 0.2). When SUA was modeled as an explanatory variable for vascular markers, it directly associated with cIMT and inversely with Cdist in age- and sex-adjusted analysis. After further adjustments for BMI or glomerular filtration rate, these relations were reduced to non-significance. No associations were found between SUA and FMD or the presence of a carotid plaque. Mendelian randomization analyses using known genetic variants for BMI and SUA confirmed that BMI is causally linked to SUA and that BMI is a significant confounder in the association between SUA and cIMT.

Conclusion

SUA is associated with cardiovascular risk markers in young adults, especially BMI, but we found no evidence that SUA would have an independent role in the pathophysiology of early atherosclerosis.

Introduction

Higher levels of serum uric acid (SUA) have been associated with coronary artery disease (CAD) [1], [2], [3], coronary calcification [4], [5], [6], carotid atherosclerotic plaques [7], increased carotid intima-media thickness (cIMT) [8], arterial stiffness [9] and with the metabolic syndrome [10], [11]. SUA is produced in humans as an end product of purine metabolism, and impaired urate homeostasis is a causal factor in gout [12]. The role of SUA in the pathophysiology of atherosclerosis is ambiguous and not fully understood. SUA has been suggested be anti-atherogenic and to counterbalance the oxidative stress in the early phases of the atherosclerosis [13], [14], and the potential link between SUA and cardiovascular risk may depend on its antioxidative capacity [12], [13], [14]. In contrast, association studies of SUA with risk markers of atherosclerosis have suggested that SUA is an independent risk factor in atherosclerosis [1], [3], [4], [5], [6], [7], [8], [9]. However, in some studies the relations between SUA and the markers of atherosclerosis have been confounded by other cardiovascular risk markers such as obesity indices [3], [4], [15], [16], [17], [18].

To clarify the role of SUA in preclinical atherosclerosis, we examined the correlates of SUA concentration and studied the associations between SUA and ultrasonographically measured markers of vascular structure and function, including carotid artery intima-media thickness (cIMT), carotid plaque, carotid distensibility (Cdist) and brachial flow-mediated dilatation (FMD), in a large well-defined cohort of 1985 young adult Finns (age 30–45 years). In addition to conventional regression analysis, we used uric acid- and BMI-associated genetic variants in instrumental variables analyses (Mendelian randomization) [19], [20], [21] to study the causal relations between SUA, BMI and cIMT.