Scheepers L.E.J.M. 1, Boonen A. 1, Pijnenburg W. D. 2, Bierau J. 3, Staessen J.A. 2, 4, Stehouwer C.D.A. 5, Thijs C. 2, Arts I.C.W. 6
1Rheumatology, CAPHRI, Maastricht University, The Netherlands. 2Epidemiology, Maastricht University, The Netherlands. 3Clinical Genetics, Maastricht University Medical Center, The Netherlands. 4Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven, Department of Cardiovascular Diseases, Leuven, Belgium. 5 Internal Medicine, CARIM, Maastricht University Medical Center, The Netherlands. 6 Epidemiology, CARIM, CAPHRI, and MaCSBio, Maastricht University, The Netherlands.
Background: Elevated uric acid (UA) concentrations have been associated with high blood pressure (BP) in adults and children. An increased production of UA by the enzyme xanthine oxidoreductase (XOR), which is accompanied by the generation of reactive oxygen species, is a putative underlying mechanism that has so far scarcely been studied. We hypothesize that an increased XOR activity leads to a relative decrease in the more upstream metabolites. Thus, lower hypoxanthine vs. xanthine, lower hypoxanthine vs. UA, and lower xanthine vs. UA concentrations, resulting in higher ratios of xanthine/hypoxanthine, UA/xanthine, and UA/hypoxanthine.
Objectives: Study the association between (i) the purine metabolites UA, hypoxanthine, and xanthine and (ii) the ratios of the three different purine metabolites as proxy measures for UA production, with systolic (SBP) and diastolic blood pressure (DBP). Methods: Cross-sectional analyses were performed in a subset of 246 children from the Dutch Koala Birth Cohort Study. During a home visit, a nurse collected a venous blood sample and measured BP three times. Furthermore, parents were instructed to measure their child’s BP on three consecutive days, in the morning and evening. Generalized estimating equations was used for analysis while controlling for sex, age, BMI, recruitment group, place and mode of delivery (hospital vs. home; natural vs. caesarean section), maternal smoking during pregnancy (active and passive), physical activity and dietary intake at four years of age (total energy, energy from carbohydrates and protein, fibre).
Results: At a mean age of 7.1 years, mean plasma concentrations were 202.8 µmol/L (SD 37.7) for UA, 4.60 µmol/L (SD 6.93) for hypoxanthine, and 0.53 µmol/L (SD 0.17) for xanthine. Average BP was 104.3 mm Hg (SD 10.0) systolic and 63.4 mm Hg (SD 10.6) diastolic. Higher ratios of UA/xanthine (adj. β 0.01 mm Hg; 95% CI, 0.00 to 0.02; P=0.03) and xanthine/hypoxanthine (adj. β 0.11 mm Hg; 95% CI, 0.01 to 0.21; P=0.03) were associated with higher DBP, but not with SBP. UA, xanthine, and hypoxanthine concentrations and the ratio UA/hypoxanthine were not associated with SBP nor DBP (P ≥0.05).
Conclusions: In multivariable-adjusted analyses, DBP in children was significantly associated with the ratios of UA/xanthine and xanthine/hypoxanthine, which we hypothesized to be proxies for UA production. The ratio UA/hypoxanthine and the purine metabolite concentrations were not associated with BP.