Background/Purpose: Both serum urate-associated genetic variants and body mass index (BMI) are associated with gout risk. The aim of this study was to systematically examine whether serum urate-associated genetic variants differ in their influence on gout risk according to BMI, and to test for interactions between these genetic variants and BMI.

Methods: This research was conducted using the UK Biobank Resource. Participants of European ethnicity, aged 40-69 years, and with genome-wide genotypes were included.  Gout was defined using a validated definition (self-report of gout or urate-lowering therapy use).  Medication use and co-morbidity data were collected via self-report.  Participants were divided into three BMI groups (BMI < 25 kg/m² [low/normal], 25 kg/m² ≤ BMI < 30 kg/m² [overweight], and BMI ≥ 30 kg/m² [obese]). The 30 serum urate-associated SNPs reported by Kottgen et al. (Nature Genetics 2013) in the large ( >140,000 European participants) Global Urate Genetics Consortium GWAS were tested for their association with gout according to BMI group.  A weighted genetic risk score (GRS) for gout risk was calculated to model the cumulative effects for the 30 variants.  Gene-BMI interactions for gout association were tested using a genetic risk score (GRS) and individual SNPs by logistic regression, adjusting for age, sex, diuretic use, renal failure, diabetes mellitus, hypertension, hypercholesterolemia, alcohol intake and smoking.

Results: Data were available for 358,728 individuals, including 7,311 gout cases (2.0%). Gout was present in 634 (0.5%) individuals in the low/normal BMI group, 3100 (2.0%) in the overweight BMI group, and 3577 (4.3%) in the obese BMI group. Mean GRS was higher in those with gout compared to those without gout in the low/normal BMI group (mean [SD] 1.82 [0.29] vs 1.65 [0.27], P = 2.45×10^-60), overweight BMI group (mean [SD] 1.83 [0.27] vs 1.65 [0.27], P < 1×10^-300), and obese BMI group (mean [SD] 1.80 [0.27] vs 1.64 [0.27], P = 6.43×10^-261).  Compared with a lower GRS (< mean), a higher GRS (≥ mean) was positively associated with gout in all BMI groups (Figure).  A GRS-BMI interaction was observed, due to a mildly attenuated effect of a higher GRS on gout risk in the obese BMI group compared to the overweight BMI group (interaction P = 0.046). There was no GRS-BMI interaction for comparisons between the low/normal and overweight BMI groups, nor between the low/normal and obese BMI groups.  No individual SNP-BMI interactions for gout were observed.

Conclusion: In individuals of European ancestry, the association of genetic factors is mildly attenuated in individuals with obesity compared to overweight. However, even for those with obesity, genetic variants have a strong effect on gout risk.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/do-serum-urate-associated-genetic-variants-differentially-contribute-to-gout-risk-according-to-body-mass-index-analysis-of-the-uk-biobank/