Genetics Drive Gout Risk Far More Than Diet

Janis C. Kelly

October 10, 2018

The assumption that gout is mainly caused by diet is wrong, according to a meta-analysis of diet and genetic variants in over 16,000 subjects. The analysis, which was published online today in BMJ, suggests that even the most "gout associated" foods and diets accounted for less than 1% of variance in serum urate levels, while nearly 24% of variance was explained by genetic factors.

"Our results challenge widely held community perceptions that hyperuricaemia is primarily caused by diet, showing that genetic variants have a much greater contribution to hyperuricaemia in the general population than dietary exposure," write Tanya J. Major, PhD, and colleagues from University of Otago, New Zealand, and colleagues.

"People with gout often experience stigma from the societal misconception that gout is a condition caused by dietary habits and an unhealthy lifestyle, a view which is also pervasive among healthcare professionals and in portrayals of gout in lay media," write Lorraine Watson, PhD, and Edward Roddy, MD, from Keele University, UK, in an accompanying editorial.

"As a result, patients known to have gout are often reluctant to seek help for fear that they will not be taken seriously or will be blamed for their lifestyle habits.... The study by Major and colleagues provides important evidence that much of patients' predisposition to hyperuricaemia and gout is non-modifiable, countering these harmful but well established views and practices and providing an opportunity to address these serious barriers to reducing the burden of this common and easily treatable condition."

Major and colleagues performed a meta-analysis of cross-sectional food frequency data from five US cohort studies. They systematically analyzed individual foods for associations with serum urate levels and compared the variances associated with dietary factors to those associated with common, genome-wide single-nucleotide variants.

The researchers also note that heritable differences include not only those directly associated with serum urate levels but also to differences in food preferences that might contribute to gout risk, such as consumption of coffee, alcohol, or sugar sweetened beverages.

The meta-analysis included 16,760 individuals of European ancestry (8414 men and 8346 women) from the US, all older than 18 years, without kidney disease or gout, and not taking urate lowering or diuretic drugs. The main outcome measures were average serum urate levels and variance in serum urate levels. Mutivariable analyses included serum urate, dietary survey data, potential confounders (sex, age, body mass index, average daily calorie intake, years of education, exercise levels, smoking status, and menopausal status), and genome-wide genotypes. To assess genetic risk, the team used 30 gene variants that have been previously associated with serum urate.

In the diet analysis, the researchers identified seven foods associated with raised serum urate levels, including beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb).

"The food items with the strongest urate raising effect (beer and liquor) were associated with a 1.38 μmol/L increase in serum urate per serving per week, equating to a 9.66 μmol/L (0.16 mg/dL) increase per daily serving."

They also identified eight foods associated with reduced serum urate levels, including eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits.

Diet scores were constructed on the basis of four different healthy diet guidelines; three were associated with lower serum urate levels, and one was associated with raised serum urate levels, but none of these scores explained more than ≤0.3% of the variance in serum urate.

Individually, the 14 food items associated with serum urate variance explained 0.06% to 0.99% of the variation; summed, they explained 3.28% of the variation, and the diet scores explained less of the variation than the most strongly associated individual food item.

"In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation," the authors write. This included 23.8% in the male cohort and 40.3% in the female cohort.

Watson and Roddy comment, "Despite the authors' caution against extrapolating their findings [to non-European subjects or to those with evident gout], it is unlikely that the cause of hyperuricaemia in the studied populations is substantially different to those with clinically evident gout. The study does not provide evidence to support a change in guideline recommendations that patients with gout should modify their diet to avoid consuming certain high risk foods excessively; it does have other broad implications for people with gout and those who care for them."

Specifically, Watson and Roddy explain that gout is often poorly managed, that two thirds of patients are not prescribed urate-lowering drugs, and that only a minority of patients increase the dose to the level required to achieve the low serum urate level needed to rid the body of urate crystals, prevent flares, and shrink tophi.

They conclude, "The reasons for poor management of gout are not fully understood, but patients' and practitioners' suboptimal understanding of gout, its causes, and treatment are considered to be important factors."

The study was supported by the Health Research Council of New Zealand and the University of Otag. Co author Nicola Dalbeth, MD, has received consulting fees, speaker fees, or grants from the following companies that have developed or marketed urate-lowering drugs for management of gout: Takeda, Ardea Biosciences/AstraZeneca, Cymabay/Kowa, and Crealta/Horizon. Tony R. Merriman, PHD, has received grants from Ardea Biosciences/AstraZeneca and Ironwood Pharmaceutical.

BMJ. Published online October 10, 2018. Full text, Editorial

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