Study Links Gout and GCKR Gene

Results from a recent systematic review and meta-analysis of the relation between single-nucleotide polymorphism (SNP) in the GCKR gene and gout indicate 4 individual SNPs are directly associated with and act as genetic risk factors for the disease.

Thanks to the recent development of genome-wide association studies, gout has been directly connected to 28 genome-wide significant loci. These loci, including GCKR and ABCG2, are associated with serum urate concentrations, the elevation of which can cause gout.2

Despite this, very little research has been conducted to calculate an effect size for GCKR’s association with gout. Given the gene’s encoding as a member of the GCKR subfamily of the Sugar Isomerase protein family and its role in phosphorylating glucose in the glycolytic pathway, its importance in maintaining blood glucose homeostasis is well known. In fact, recent studies have been explicitly contradictory in measuring the degree of association between gout and GCKR.1

“To resolve this paradox, meta-analysis was needed to calculate the pooled effect size for the association of single nucleotide polymorphism (SNP) of GCKR with gout,” wrote Zheng Xi, department of orthopedic one ward, the Second Affiliated Hospital of Qiqihar Medical University, and colleagues.1

The team examined relevant literature from PubMed, Web of Science, Embase, and the Cochrane Library. Inclusion criteria included the following:

• The study was case-control or cohort in structure
• The study examined a case group of patients diagnosed with gout
• The study included a description of the gene frequency or genotype frequency of the SNPs of the GCKR gene
• Patients were selected with no special age or gender restriction

Exclusion criteria included a population younger than 18 years, unreported gene frequencies and genotype frequencies of SNPs for either case or control groups, and missing or incomplete data.1

A total of 124 studies were initially included; 40 duplicates were removed, and 46 were removed after screening titles and abstracts. The remaining 38 articles were read in full, and a final total of 11 articles were chosen for the study: 10 case-control studies and 1 cohort study. A total of 182,628 patients were included.1

Investigators found 4 SNPs (rs780094, rs1260326, rs6547694, and rs780093) in the GCKR gene were associated with gout. Allelic models were then utilized to investigate the degree of association, which was found to be statistically significant overall (odds ratio [OR], 1.27; 95% CI, 1.21-1.34; P <.001).1

The team then analyzed each locus individually, which indicated the effects of each were not significantly different across populations. They also made use of dominant and recessive models for the rs780094 locus, which contained the most datasets, to investigate its association with gout. The pooled results indicated a significant correlation (dominant model: OR, 1.32; 95% CI, 1.12-1.52; P <.001; recessive model: OR, 1.3; 95% CI, 1.16-1.63; P <.001).1

Although these data indicate a very high correlation between gout and the SNPs of GCKR, investigators did note a few limitations. Most notable was the moderate heterogeneity emerging during the calculation of effect sizes between all SNPs and gout as well as meta-regression analysis implying the study publication year was the source of heterogeneity, as significant differences in effect sizes appeared across publication years.1

Additionally, there was only 1 study examining rs6547692, which severely limited investigators’ ability to compare across populations or to identify the pooled effect sizes.1

“Identification of genetic variants is necessary to achieve etiological diagnosis and precision treatment of gout,” wrote Xi and colleagues. “In the future, more complex and precise functional studies are needed to elucidate the mechanisms by which these genes affect the occurrence of gout.”1

References

1. 1: Xi Z, Dong P. The association between genetic polymorphisms in GCKR and gout: A systematic review and meta-analysis. Medicine (Baltimore). 2025;104(21):e42447. doi:10.1097/MD.0000000000042447

2. 2: Köttgen A, Albrecht E, Teumer A, et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013;45(2):145-154. doi:10.1038/ng.2500