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Abstract
BackgroundPrevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is therefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels.MethodsFour European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was done in the UK Biobank using dietary pattern-associated genetic variants as exposure and serum urate levels as outcome.ResultsAdherence to dietary recommendations, BMI (< 25 kg/m2), and absence of the SLC2A9 rs12498742 urate-raising allele produced PAFs for HU of 20 to 24%, 59 to 69%, and 57 to 64%, respectively, in the three non-gout cohorts. In the gout cohort, diet, BMI, SLC2A9 rs12498742 and ULT PAFs for HU were 12%, 49%, 48%, and 63%, respectively. Mendelian randomisation demonstrated weak causal effects of four dietary habits on serum urate levels (e.g. preferentially drinking skim milk increased urate, β = 0.047 mmol/L, P = 3.78 × 10−8). These effects were mediated by BMI, and they were not significant (P ≥ 0.06) in multivariable models assessing the BMI-independent effect of diet on urate.ConclusionsDiet has a relatively minor role in determining serum urate levels and HU. In gout, the use of ULT was the largest attributable fraction tested for HU.
Highlights
Hundreds of genetic variants are associated with serum urate levels [1,2,3], and observational studies have associated individual dietary factors and overall eating habits [9,10] with urate levels, along with other environmental and endogenous factors
Our previous study [10] concluded, using percent variance explained, that common genetic variants have a greater contribution to urate levels in the non-gout population than overall diet
The summed percent variance for the 30 genetic variants for urate levels was 8.7%, considerably greater than the variance explained by the Dietary Approaches to Stop Hypertension (DASH) diet [10]
Summary
Hundreds of genetic variants are associated with serum urate levels [1,2,3], and observational studies have associated individual dietary factors (e.g. alcohol, sugarsweetened beverages, coffee, red-meat consumption [4,5,6,7,8]) and overall eating habits [9,10] with urate levels, along with other environmental (e.g. diuretic use [11, 12]) and endogenous factors (e.g. age and sex [13]). Understanding the importance of risk factors and their causal relationship (if any) with HU is critical in developing strategies for the prevention of HU and gout. Any attempts to draw conclusions with respect to causality, including using causal language/ inferences, even from an accumulation of studies, misrepresents the evidence [14]. In this context, we note that gout is a multi-stage process beginning with HU, progressing to deposition of monosodium urate crystals and culminating in an innate immune response to crystals [15]. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is important in the prevention of gout. We use Mendelian randomisation to test for the causality of diet in urate levels
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