Genetics of serum urate concentrations and gout in a high-risk population, patients with chronic kidney disease

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.

Cell lineage-specific methylome and genome alterations in gout

“…All participants self-identified as Han Chinese. Previous genetic studies also utilized self-reported gout [ 12 , 76 , 77 ] and demonstrated that self-reporting of physician-diagnosed gout resulted in high sensitivity and precision [ 78 ].…”

Clinical epidemiological analysis of cohort studies investigating the pathogenesis of kidney disease

“…Biomaterials such as DNA, serum, plasma, and urine are collected using standardized methods to identify biomarkers associated with CVD incidence and CKD progression [ 17 ]. In addition to epidemiological topics such as blood pressure [ 18 ], heart failure [ 19 ], dietary patterns [ 20 ], and gout [ 21 ], biomarkers and genes such as urine 6-bromotryptophan [ 22 ], serum uromodulin [ 23 ], GWAS of urate and gout [ 24 ], telomere length [ 25 ], and other biomarkers and genes have been actively investigated.…”

<p>The Importance of Tubular Function in Chronic Kidney Disease</p>

“…Additionally, since URAT1 is a member of the OATs, and four of them have been localized at the basolateral and luminal areas of the PT, studies have suggested that all of them may mediate urate transport in both the renal secretion and reabsorption. Besides, a renal-specific transporter RST, which is mainly localized at the apical surface of the PT may also contribute to PT urate reabsorption 13,14. Increased oxidative stress and hypovolemia stimulate urate tubular reabsorption, with angiotensin II, epinephrine and insulin hormones acting as potential mediators 15.…”