Abstract
BackgroundSerum urate is the most abundant small molecule with antioxidant properties found in blood and the epithelial lining fluid of the respiratory system. Moderately raised serum urate is associated with lower rates of lung cancer and COPD in smokers but whether these relationships reflect antioxidant properties or residual confounding is unknown.MethodsWe investigated the observational and potentially causal associations of serum urate with lung cancer incidence and FEV1 using one-sample Mendelian randomization (MR) and the UK Biobank resource. Incident lung cancer events were identified from national cancer registries as FEV1 was measured at baseline. Observational and genetically instrumented incidence rate ratios (IRRs) and risk differences per 10,000 person-years (PYs) by smoking status were estimated.ResultsThe analysis included 359,192 participants and 1,924 lung cancer events. The associations between measured urate levels and lung cancer were broadly U-shaped but varied by sex at birth with the strongest associations in current smoking men. After adjustment for confounding variables, current smoking men with low serum urate (100 µmol/L) had the highest predicted lung cancer incidence at 125/10,000 PY (95%CI 56–170/10,000 PY) compared with 45/10,000 PY (95%CI 38–47/10,000 PY) for those with the median level (300 µmol/L). Raised measured urate was associated with a lower baseline FEV1. The MR results did not support a causal relationship between serum urate and lung cancer or FEV1.ConclusionsWe found no evidence that serum urate is a modifiable risk factor for respiratory health or lung cancer.
Highlights
Serum urate is the most abundant small molecule with antioxidant properties found in blood and the epithelial lining fluid of the respiratory system
We examined whether participants genetically predisposed to raised urate were less likely to have a positive family history of lung cancer and a lower baseline prevalence of chronic obstructive pulmonary disease (COPD)
(See figure on page.) Fig. 2 Observational associations of serum urate with Forced expiratory volume per second (FEV1) and lung cancer incidence in regular smokers by sex adjusted for age, calendar year, ethnicity, packyears of smoking, height and recruitment centre (Model 1), for weight (Model 2) and waist circumference, alcohol consumption, exposure to smoke at home, social deprivation, air pollution levels, and intake of antioxidant supplements (Model 3)
Summary
Serum urate is the most abundant small molecule with antioxidant properties found in blood and the epithelial lining fluid of the respiratory system. Raised serum urate is associated with lower rates of lung cancer and COPD in smokers but whether these relationships reflect antioxidant properties or residual confounding is unknown. Estimates suggest as much as 50% of human blood antioxidant capacity is accounted for by the action of serum urate [8]. This has led to theories that the low cancer rates and longevity in hominids relative to other mammals are partly due to the reduction and loss of uricase activity [9]. Our group’s previous large-scale cohort study of people living in the UK found that cigarette smokers with moderately high serum urate had substantially lower rates of COPD and lung cancer [12]. The association may reflect residual confounding or reverse causation rather than antioxidant properties of urate
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