Reply to: Exploring the Interplay of Gout, Genetic Factors, and Dietary Influences

We thank Kao and colleagues for their interest in our manuscript(1) which found that both nature (i.e., genetic susceptibility) and nurture (i.e., adherence to a healthy dietary pattern) contribute to incident female gout risk, and appreciate the opportunity to expand upon some details.

First, diabetes, hypertension, and chronic kidney disease were not included in our multivariable models to avoid ‘overadjustment’ for factors which were unlikely to be true confounders. Indeed, these conditions are likely to serve as mediators (as opposed to confounders) in the causal pathway between diet and subsequent development of gout, as adherence to a Dietary Approaches to Stop Hypertension (DASH)-style diet has been associated with development of these conditions as downstream outcome variables[https://www.hsph.harvard.edu/nutritionsource/healthy-weight/diet-reviews/dash-diet/]. Regarding Kao et al’s query about potential evaluation of water intake and chicken and fish consumption on gout risk, while specific nutrients and foods have been individually associated with hyperuricemia and gout risk, it is imperative to recognize that they are often consumed concomitantly. Thus, to truly discern their synergistic effects, one must examine the comprehensive eating regimen. Evaluating food intake through dietary patterns, such as the DASH diet, provides a holistic perspective on disease prevention and management.

Second, regarding the comment on the potential ranking of attributable proportions of each cohort, it is important to note that there was very high overlap in the 95% confidence intervals (CI) between the estimates (e.g., proportion due to gene-diet interaction, 45% [95% CI, 22% to 68%]) versus that due to genetic susceptibility alone, 46% [95% CI, 36% to 56%]) and the random-effects framework to combine the cohorts was a standard approach. Regardless, the key message of our findings was that diet (alone or in combination with genetic factors) contributed to the development of the majority of excess cases of female gout (Figure 1), 55% in the NHS and 71% in the three replication cohorts. From a public health viewpoint, these findings support a healthy guideline-based diet such as the DASH for primary prevention of gout, given that diet is modifiable while genes currently are not.

Figure 1.

Modifiable vs non-modifiable proportions of excess gout risk due to genetic predisposition, DASH diet adherence, and their interactions

Third, regarding not including sodium intake in the UKBB, we found our results did not change materially with or without the UKBB cohort included (51% attributable to the gene–diet interaction in both cases). As higher sodium intake has been shown to lower serum urate levels in randomized trials, but also to raise blood pressure, no clinical or public health recommendations can be made to increase sodium intake for urate-lowering for gout prevention.

In summary, we appreciate the comments but wish the readers to take away our manuscript’s principal finding, that low adherence to a DASH-style diet amplifies the deleterious effects of genetic predisposition on risk of incident female gout, whilst this genetic predisposition can be overcome by high DASH adherence.