Abstract
We evaluated genetics of hyperuricemia and gout, their interaction with kidney function and medication intake in chronic kidney disease (CKD) patients. Genome-wide association studies (GWAS) of urate and gout were performed in 4941 CKD patients in the German Chronic Kidney Disease (GCKD) study. Effect estimates of 26 known urate-associated population-based single nucleotide polymorphisms (SNPs) were examined. Interactions of urate-associated variants with urate-altering medications and clinical characteristics of gout were evaluated. Genome-wide significant associations with serum urate and gout were identified for known loci at SLC2A9 and ABCG2, but not for novel loci. Effects of the 26 known SNPs were of similar magnitude in CKD patients compared to population-based individuals, except for SNPs at ABCG2 that showed greater effects in CKD. Gene-medication interactions were not significant when accounting for multiple testing. Associations with gout in specific joints were significant for SLC2A9 rs12498742 in wrists and midfoot joints. Known genetic variants in SLC2A9 and ABCG2 were associated with urate and gout in a CKD cohort, with effect sizes for ABCG2 significantly greater in CKD compared to the general population. CKD patients are at high risk of gout due to reduced kidney function, diuretics intake and genetic predisposition, making treatment to target challenging.
Highlights
Gout is a progressive painful debilitating disease, and the most common inflammatory arthritis in many Western countries[1]
One candidate gene study that focused on 11 urate transporters reported that the strength of association - as quantified by the association p-value - between genetic variants in ABCG2 was stronger in patients with chronic kidney disease (CKD) compared to 481 population-based individuals, while the opposite was observed for variants in SLC2A99
We investigated whether genetic effects were more clearly discernible in joints across which temperature, weight pressure or usage strain may differ for the genome-wide significant urate-associated index single nucleotide polymorphisms (SNPs) at ABCG2 and SLC2A9
Summary
Gout is a progressive painful debilitating disease, and the most common inflammatory arthritis in many Western countries[1]. About ~25% of CKD patients from the prospective German Chronic Kidney Disease (GCKD) study reported a physician diagnosis of gout at study baseline and two thirds of patients were hyperuricemic[7]. This high prevalence of gout is most relevant given that CKD affects about 10% of the adult population in many countries[8]. Interactions between medications influencing serum urate concentrations and commonly prescribed in CKD were evaluated, and associations between genetic risk variants and clinical characteristics of gout were examined
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