Genome-Wide Association Study of CKD Progression.

SIGNIFICANCE STATEMENT: Rapid progression of CKD is associated with poor clinical outcomes. Most previous studies looking for genetic factors associated with low eGFR have used cross-sectional data. The authors conducted a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD, focusing on longitudinal data. They identified three loci (two of them novel) associated with longitudinal eGFR decline. In addition to the known UMOD/PDILT locus, variants within BICC1 were associated with significant differences in longitudinal eGFR slope. Variants within HEATR4 also were associated with differences in eGFR decline, but only among Black/African American individuals without diabetes. These findings help characterize molecular mechanisms of eGFR decline in CKD and may inform new therapeutic approaches for progressive kidney disease. BACKGROUND: Rapid progression of CKD is associated with poor clinical outcomes. Despite extensive study of the genetics of cross-sectional eGFR, only a few loci associated with eGFR decline over time have been identified. METHODS: We performed a meta-analysis of genome-wide association studies of eGFR decline among 116,870 participants with CKD-defined by two outpatient eGFR measurements of <60 ml/min per 1.73 m 2 , obtained 90-365 days apart-from the Million Veteran Program and Vanderbilt University Medical Center's DNA biobank. The primary outcome was the annualized relative slope in outpatient eGFR. Analyses were stratified by ethnicity and diabetes status and meta-analyzed thereafter. RESULTS: In cross-ancestry meta-analysis, the strongest association was rs77924615, near UMOD / PDILT ; each copy of the G allele was associated with a 0.30%/yr faster eGFR decline ( P = 4.9×10 -27 ). We also observed an association within BICC1 (rs11592748), where every additional minor allele was associated with a 0.13%/yr slower eGFR decline ( P = 5.6×10 -9 ). Among participants without diabetes, the strongest association was the UMOD/PDILT variant rs36060036, associated with a 0.27%/yr faster eGFR decline per copy of the C allele ( P = 1.9×10 -17 ). Among Black participants, a significantly faster eGFR decline was associated with variant rs16996674 near APOL1 (R 2 =0.29 with the G1 high-risk genotype); among Black participants with diabetes, lead variant rs11624911 near HEATR4 also was associated with a significantly faster eGFR decline. We also nominally replicated loci with known associations with eGFR decline, near PRKAG2, FGF5, and C15ORF54. CONCLUSIONS: Three loci were significantly associated with longitudinal eGFR change at genome-wide significance. These findings help characterize molecular mechanisms of eGFR decline and may contribute to the development of new therapeutic approaches for progressive CKD.

Genetic Variants Associated With Mineral Metabolism Traits in Chronic Kidney Disease.

CONTEXT: Chronic kidney disease (CKD) causes multiple interrelated disturbances in mineral metabolism. Genetic studies in the general population have identified common genetic variants associated with circulating phosphate, calcium, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). OBJECTIVE: In this study we aimed to discover genetic variants associated with circulating mineral markers in CKD. METHODS: We conducted candidate single-nucleotide variation (SNV) analysis in 3027 participants in the multiethnic Chronic Renal Insufficiency Cohort (CRIC) to determine the associations between SNVs and circulating levels of mineral markers. RESULTS: SNVs adjacent to or within genes encoding the regulator of G protein-coupled signaling 14 (RGS14) and the calcium-sensing receptor (CASR) were associated with levels of mineral metabolites. The strongest associations (P < .001) were at rs4074995 (RGS14) for phosphate (0.09 mg/dL lower per minor allele) and FGF23 (8.6% lower), and at rs1801725 (CASR) for calcium (0.12 mg/dL higher). In addition, the prevalence of hyperparathyroidism differed by rs4074995 (RGS14) genotype (chi-square P < .0001). Differential inheritance by race was noted for the minor allele of RGS14. Expression quantitative loci (eQTL) analysis showed that rs4074995 was associated with lower RGS14 gene expression in glomeruli (P = 1.03 × 10-11) and tubules (P = 4.0 × 10-4). CONCLUSION: We evaluated genetic variants associated with mineral metabolism markers in a CKD population. Participants with CKD and the minor allele of rs4074995 (RGS14) had lower phosphorus, lower plasma FGF23, and lower prevalence of hyperparathyroidism. The minor allele of RGS14 was also associated with lower gene expression in the kidney. Further studies are needed to elucidate the effect of rs4074995 on the pathogenesis of disordered mineral metabolism in CKD.

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.

Association of Apparent Treatment-Resistant Hypertension With Differential Risk of End-Stage Kidney Disease Across Racial Groups in the Million Veteran Program.

[Figure: see text].