The comparative effect of exposure to various risk factors on the risk of hyperuricaemia: diet has a weak causal effect

Ruth K. G. Topless, Tanya J. Major, Jose C. Florez, Joel N. Hirschhorn, Murray Cadzow, Nicola Dalbeth, Lisa K. Stamp, Philip L. Wilcox, Richard J. Reynolds, Joanne B. Cole, Tony R. Merriman

Prevention 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. Four 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. Adherence 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. Diet 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.