A Genetic Marker of Uric Acid Level, Carotid Atherosclerosis, and Arterial Stiffness: A Family-Based Study

BACKGROUND: Hyperuricemia associates with atherosclerosis complications, but it is uncertain whether this relationship is causal in nature. The urate transporter GLUT9 (encoded by the SLC2A9 gene) is a major genetic determinant of serum uric acid level in humans. Because polymorphisms are distributed randomly at mating (Mendelian randomization), studies based on GLUT9 polymorphisms may provide unconfounded assessment of the nature of the link between uric acid and atherosclerosis. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Family-based study including 449 individuals in 107 families in a genetically homogeneous population in Southern Italy. FACTOR: Serum uric acid level, rs734553 allele, and age. OUTCOME: Ultrasound biomarkers of atherosclerosis (intima-media thickness [IMT] and internal diameter) and pulse wave velocity (PWV). RESULTS: Serum uric acid level was dose-dependently associated with the T allele of rs734553, a polymorphism in SLC2A9 (P=8×10(-6)). Serum uric acid level was a strong modifier of the relationship between age and IMT in fully adjusted analyses (?=0.33; P=0.01), whereas no such relationship was found for internal diameter (?=-0.15; P=0.3) or PWV (?=0.10; P=0.6). The T allele coherently associated with carotid IMT, internal diameter, and PWV and emerged as an even stronger modifier of the age-IMT and age-internal diameter relationships in both crude and fully adjusted (?=0.40 [P<0.001] and ?=0.48 [P=0.003], respectively) analyses. LIMITATIONS: This is a hypothesis-generating study. CONCLUSIONS: Results in this family-based study implicate uric acid as an important modifier of the age-dependent risk for atherosclerosis. Trials testing uric acid-lowering interventions are needed to prove this hypothesis.