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Causal Relationship Observed Between Obesity, Serum Urate, & Gout

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03/08/2023
rheumatologyadvisor.com

An intrinsic link underlying obesity, serum urate levels, and gout was observed in a genome-wide cross-trait analysis published in Rheumatology (Oxford).

Trends indicate the role of obesity in the etiology of gout. In addition, epidemiologic and clinical evidence has demonstrated an association between obesity and gout.

The researchers sought to explore the association between obesity-related traits, serum urate levels, and gout.

Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) were the 3 obesity-related traits included as exposures. The primary study outcome of interest was gout, and the secondary study outcome of interest was serum urate level.

The researchers collected summary statistics from the largest genome-wide association studies (GWAS) of obesity. They analyzed data from the UK Biobank and the Genetic Investigation of Anthropometric Traits Consortium (GIANT) from individuals of European ancestry. In addition, statistics from the largest GWAS of gout and serum urate levels from the Chronic Kidney Disease Consortium were collected. Further, the researchers conducted a Cross Phenotype Association (CPASSOC) analysis to identify pleiotropic single-nucleotide polymorphisms (SNPs) that affected BMI WHR.

Results of the study showed that both BMI and WHR showed a positive, statistically significant genetic association with gout (P =6.62×10-7 and P =6.26×10-7, respectively).

Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a causal relationship between obesity, serum urate, and gout, highlighting an intrinsic link underlying these complex traits.

Excluding the impact of BMI on WHR, the positive genetic association decreased but still remained statistically significant (WHRadjBMI: (P =6.08×10-3).

Similar patterns were reported with serum urate, in which all estimates were more distinct in both magnitude and significance.

Following adjustment for multiple testing, with the whole genome partitioned into 1703 independent regions, a significant local signal was identified for BMI and gout, with 1 significant region 4 q22.1 observed for obesity (BMI) and gout (P <.05).

The global and local shared genetic basis was further supported by the multiple pleiotropic loci detected in the cross-phenotype association analysis, multiple shared gene-tissue pairs revealed in transcriptome-wide association analyses, and the causal relationships that were revealed by Mendelian randomization (gout: odds ratio [OR], 1.66; 95% CI, 1.45-1.88 and WHR-gout: OR, 1.57; 95% CI, 1.37-1.81).

Several study limitations were noted. Although gout is known to be more common among men than women, sex-specific analyses were not conducted due to limited available data; the lack of generalizability of the results to other ethnicities except European; and the genes identified in the study depended entirely on functional datasets and algorithms. The researchers noted that in-depth experimental studies are required to better understand the underlying mechanisms.

However, they concluded, “[The] genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a causal relationship between obesity, serum urate, and gout, highlighting an intrinsic link underlying these complex traits.”

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Schedule14 Apr 2024