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New Research Identifies Genes Associated With Gout RIsk

Researchers identified 2 genes associated with increased risk and 3 associated with decreased risk.

New Research Identifies Genes Associated With Gout RIsk

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New research has identified several genes associated with the pathogenesis of gout, which may inform potential therapeutic targeting for its treatment.1

“Gout is commonly diagnosed as inflammatory arthritis characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals, causing intense pain and joint damage, often leading to deformity. As a multifactorial metabolic disorder, the primary risk factors for gout include hyperuricemia, genetic predispositions, and dietary influences,” lead investigator Yu Wang, Graduate School of Jiangxi University of Traditional Chinese Medicine, Nanchang, China, and colleagues wrote.1 “Research shows that gout’s pathogenesis mainly results from abnormal uric acid metabolism—due to either reduced excretion or increased production—which precipitates MSU crystal deposits in joints, triggering inflammation.”

Wang and colleagues used the Summary Data-based Mendelian Randomization (SMR) approach to analyze expression quantitative trait loci (eQTL) data from blood and renal tissues and genome-wide association study (GWAS) data related to gout. They conducted heterogeneity testing with the HEIDI test and adjusted for the False Discovery Rate (FDR). They sourced blood cis-eQTL data from the eQTLGen Consortium, renal tissue data from the V8 release of the GTExeQTL summary, and gout GWAS data from the FinnGen Documentation of the R10 release.1

The investigators identified 14 gene probes in the eQTLGen blood summary-level data that were significantly associated with gout after SMR analysis. These genes are ENSG00000169231 (labeled THBS3; PSMR, 4.16 × 10−13), ENSG00000231064 (labeled THBS3-AS1; PSMR = 1.88 × 10−8), ENSG00000163463 (labeled KRTCAP2; PSMR, 3.88 × 10−6), ENSG00000172977 (labeled KAT5; PSMR, 1.70 × 10−5), and ENSG00000161395 (labeled PGAP3, PSMR = 3.24 × 10−5). They found that increased expression of KRTCAP2 and PGAP3 were associated with an increased risk of gout, and increased expression of THBS3, THBS3-AS1, and KAT5 is associated with a reduced risk of gout. They did not find any significant gene associations in renal tissue with gout, which they stated was likely due to the limited sample size of the kidney tissue.1

“In summary, this study combined GWAS and eQTL data related to gout, identifying 14 genes that may be involved in the pathogenesis of the disease. These genes are implicated in regulating inflammatory responses, immune reactions, and uric acid metabolism. However, further research is necessary to confirm the functions of these genes in gout and to investigate other genes related to the disease’s mechanisms,” Wang and colleagues concluded.1

Other recent research looking into associations with gout found that insulin resistance, or a higher triglyceride glycemic (TyG) index, was associated with an increased likelihood of gout in adults in the United States. The investigators conducted a cross-sectional study of adults with complete TyG index and gout data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2017.2

after adjusting for all covariates, TyG index was positively associated with gout, with each unit increase in TyG index associated with 40% higher odds of gout (odds ratio (OR), 1.40 [95% CI, 1.82–2.66]; P <.0001). Accordingly, participants in the highest TyG index tertile group were at high risk of gout (odds ratio (OR), 1.64 [95% CI, 1.06–2.54]; P = .03) compared with those in the lowest tertile group. Investigators found no significant effects of age, race, marital status, PIR level, education, BMI, smoking status, drinking status, hypertension, and diabetes mellitus status on the association between TyG index and gout (all P >.05).2

REFERENCES
1. Wang Y, Chen J, Yao H, Li Y, Xu X, Zhang D. Mendelian randomization analysis identified potential genes pleiotropically associated with gout. Front Genet. 2024;15:1426860. doi:10.3389/fgene.2024.1426860
2. Li, T, Zhang, H, Wu, Q, Guo S, Hu W. Association between triglyceride glycemic index and gout in US adults. J Health Popul Nutr. 2024;43 (115). doi: 10.1186/s41043-024-00613-4
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