Riku Takei, Nicholas A. Sumpter, Megan P. Leask, Tony R. Merriman
Affiliation(s):
University of Alabama at Birmingham
Objective: To investigate the genetic colocalization of gout-associated genetic loci with genetic control of the metabolome, and to investigate the causal role of metabolites in gout.
Methodology: GWAS data for 1,083 plasma metabolites were downloaded[1] and tested for genetic colocalization with gout genetic association data from a recent GWAS[2]. Restricting the locus region to lead SNP ±500kb, genetic colocalization analysis was carried out for 276 gout loci for each of the 1,083 metabolite GWAS data using the ‘coloc’ R package. Colocalization occurred if the posterior probability of colocalization was ≥ 0.8. Ten metabolites with the highest number of loci colocalized with gout were then tested for a causal role in gout by Mendelian randomization (MR) using the ‘MendelianRandomization’ package in R. The inverse variance-weighted (IVW) and weighted median (WM) methods were used to test for causality, and the MR-Egger method was used to test for pleiotropy.
Results: Ten metabolites colocalized with gout genetic association signals in at least five loci: urate (positive control), retinol (vitamin A), diacylglycerol, androstenediol disulfate, androsterone sulfate, threonine, glutamine, pyroglutamine, serine, and alanine. Four of these metabolites showed evidence of causality for gout in at least one of the MR methods used; urate (PIVW = 6.01e-5 and PWM = 3.19e-25), androsterone sulfate (PIVW = 7.71e-3 and PWM = 5.87e-10), diacylglycerol (PIVW = 1.42e-2 and PWM = 3.96e-5), and glutamine (PIVW = 0.46 and PWM = 3.95e-3). Urate and androsterone sulfate showed evidence of pleiotropy (MR-Egger intercept P = 2.19e-2 and 5.13e-3, respectively). Conclusions: Diacylglycerol, glutamine, and androsterone sulfate showed evidence of causality for gout. Glutamine is involved in the formation of phosphoribosylamine in de novo purine biosynthesis, a key precursor molecule of urate synthesis. Furthermore, glutamine can be converted into glutamate via glutaminolysis and fed into the tricarboxylic acid cycle, which produces substrate for trained immunity of innate immune cells[3]. There is increased macrophage responsiveness with loss of diacylglycerol kinase alpha [4] (an enzyme responsible for converting diacylglycerol into phosphatidic acid) and it has been hypothesized that the abundance of diacylglycerol species causes increased activation of protein kinase C, which in turn contributes to macrophage responsiveness. Androsterone sulfate is a breakdown metabolite of testosterone. How it could play a causal role in gout is not clear, although it could indicate a causal role for testosterone.
1. Yin, X. et al. Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci. Nat. Commun. 13, 1644 (2022). 2. Major, T. J. et al. A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout. 2022.11.26.22281768 Preprint at https://doi.org/10.1101/2022.11.26.22281768 (2022). 3. Arts, R. J. W. et al. Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell Metab. 24, 807–819 (2016). 4. Manigat, L. C. et al. Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness. Front. Immunol. 12, (2021).