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Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD., Competing Interests: Declaration of interests C.E.H. was awarded an MRC iCASE studentship (MR/P016065/1), which was cofunded by GSK and the MRC for the duration of the study. GSK are undertaking clinical development into a novel PHI and have given permission to publish this work alongside an internal review of the manuscript. A.Y.C. is an employee of GSK, is a shareholder of GSK stock, and was involved in the study design, interpretation of the data, and writing of the paper. V.V.P. was an employee of GSK at the time of the study conception and design. He was involved in interpreting the data and writing of the paper and is a shareholder of GSK and Roche Holding AG stocks. D.M.W. was an employee of GSK at the time of the study conception and design and was involved in the interpretation of the data and writing of the paper. H.L.L. and M.A.N. received support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH). They were involved in data analysis and review of the manuscript. N.V. is a full-time employee of Regeneron Pharmaceutical Inc. and receives stock options and restricted stock units as compensation. D.D.J. received support from the Center of Human Health and the Environment P30ESO25128 grant. F.I. is an AbbVie employee and receives stocks from AbbVie, which has not been involved in this work at any level., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.

Background: We developed a genetic risk score (GRS) and examined whether the GRS may predict incident stage 3 chronic kidney disease (CKD) independent of common clinical risk factors., Method: The present study included 2,698 individuals who attended the 15th (1977 to 1979) and the 24th exams (1995 to 1998) in the Framingham Original cohort or the 6th (1995 to 1998) and the 8th exams (2005 to 2008) in the Framingham Offspring cohort. A weighted GRS was constructed combining 53 single nucleotide polymorphisms (SNPs) associated with lower creatinine-based estimated glomerular filtration rate (eGFR). Stage 3 CKD was defined as eGFR <60 mL/min/1.73 m 2 , and incident cases were identified at follow-up after excluding prevalent cases at baseline., Results: A total of 292 incident cases and 2,406 non-cases were identified over, on average, 11 years of follow-up. After adjustment for sex, age, cohort, baseline eGFR, hypertension, diabetes, and dipstick proteinuria, the odds ratio of incident stage 3 CKD was 1.37 (95%CI: 1.02-1.83) per 10 alleles of the GRS (P = 0.04). There was no statistically significant difference between the C-statistic without and with inclusion of the GRS (0.783 and 0.785, respectively; P = 0.39)., Conclusions: A GRS developed based on 53 SNPs associated with reduced eGFR was prospectively associated with incident stage 3 CKD. However, this score did not substantially improve discrimination of stage 3 CKD beyond the common clinical risk factors.

Background: No observational studies have directly considered dietary guidelines when examining the prospective association between dietary intake and kidney measures., Study Design: Prospective cohort study., Setting & Participants: We examined participants who attended examinations 7 (1998-2001) and 8 (2005-2008) in the Framingham Offspring Cohort., Predictors: Individual components of Dietary Guidelines for Americans Adherence Index (DGAI) that reflect adherence to key dietary recommendations based on the 2005 guideline., Outcomes & Measures: The primary outcome was incident low estimated glomerular filtration rate (eGFR) at follow-up after exclusion of prevalent low eGFR at baseline. Low eGFR was defined as serum creatinine-based eGFR<60mL/min/1.73m 2 ., Results: Among 1,822 participants (mean age, 59.4 years; 54.6% women), 181 incident cases of low eGFR were identified. After adjustment for potential confounders, compared to optimal adherence to meat and legume recommendations, low adherence was associated with higher odds of incident low eGFR (P for trend = 0.01); ORs in the lowest and intermediate adherence categories were 2.98 (95% CI, 1.13-7.92) and 1.65 (95% CI, 1.02-2.66), respectively. Low adherence to dairy product recommendations was also associated with higher odds of incident low eGFR compared to optimal adherence (P for trend = 0.03); ORs in the lowest and intermediate adherence categories were 1.98 (95% CI, 1.03-3.82) and 1.59 (95% CI, 0.81-3.11), respectively. In addition, low adherence to meat and legume recommendations was associated with rapid eGFR decline (P for trend = 0.01), and low adherence to dairy product recommendations was associated with rapid eGFR decline (P for trend = 0.01) and incident albuminuria (P for trend = 0.03)., Limitations: The DGAI was developed based on the 2005 Dietary Guidelines for Americans., Conclusions: Better adherence to dietary recommendations for both meat and legumes and dairy products was associated with lower risk for developing adverse kidney measures., (Published by Elsevier Inc.)

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Background and Objectives: Lifestyle characteristics are modifiable factors that could be targeted as part of chronic kidney disease (CKD) prevention. We sought to determine the association of lifestyle characteristics with incident estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) and rapid eGFR decline in older adults in the United States., Methods: Prospective cohort study of Framingham Offspring participants with baseline eGFR <60 ml/min/1.73 m(2) (n = 1,802) who attended the seventh (1998-2001; baseline) and eighth (2005-2008; follow-up) examinations (mean age = 59 years, 54.8% women). Predictors included measures of diet quality, physical activity, alcohol intake, and current smoking status assessed during baseline. Outcomes were based on creatinine-based eGFR at baseline and follow-up and included incident eGFR <60 ml/min/1.73 m(2) (at follow-up) and rapid eGFR decline (annual eGFR decrease ≥3 ml/min/1.73 m(2))., Results: Over an average follow-up of 6.6 years, 9.5% (n = 171) of participants developed incident eGFR <60. A trend was observed across quartiles of diet quality, with higher levels of diet quality associated with a decreased odds ratio (OR) of incident eGFR <60 (p trend = 0.045). Higher diet quality was associated with decreased odds of rapid eGFR decline (p trend = 0.03) and was attenuated with additional adjustment (p trend = 0.07). In sensitivity analysis for rapid eGFR decline using a secondary definition (annual eGFR decrease ≥3 and incident eGFR <60), diet associations remained significant with additional adjustment (p trend = 0.04). No associations were observed with physical activity, smoking status, or alcohol intake with incident eGFR <60 or rapid eGFR decline (all p > 0.19)., Conclusions: Higher diet quality may be associated with a decreased risk of incident eGFR <60 ml/min/1.73 m(2), and rapid eGFR decline. Whether adherence to a healthy diet can prevent reduction in kidney function warrants further study., (© 2015 National Institutes of Health (NIH). Published by S. Karger AG, Basel.)

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

Background: Apolipoprotein E polymorphisms (APOE) have been associated with lowered glomerular filtration rate (GFR) and chronic kidney disease (CKD) with e2 allele conferring risk and e4 providing protection. However, few data are available in non-European ethnic groups or in a population-based cohort., Methods: The authors analyzed 5,583 individuals from the Third National Health and Nutrition Examination Survey (NHANES III) to determine association with estimated GFR by the Modification of Diet in Renal Disease (MDRD) equation and low-GFR cases. Low-GFR cases were defined as GFR <75 ml/min/1.73 m2; additionally, GFR was analyzed continuously., Results: In univariate analysis, the e4 allele was negatively associated with low-GFR cases in non-Hispanic whites, odds ratio (OR): 0.76, 95% confidence interval (CI): 0.60, 0.97. In whites, there was a significant association between increasing APOE score (indicating greater number of e2 alleles) and higher prevalence of low-GFR cases (OR: 1.21, 95%CI: 1.01, 1.45). Analysis of continuous GFR in whites found the e4 allele was associated with higher levels of continuous GFR (beta-coefficient: 2.57 ml/min/1.73 m2, 95%CI: 0.005, 5.14); in non-Hispanic blacks the e2 allele was associated with lower levels of continuous GFR (beta-coefficient: -3.73 ml/min/1.73 m2, 95%CI: -6.61, -0.84). APOE e2 and e4 alleles were rare and not associated with low-GFR cases or continuous GFR in Mexican Americans., Conclusion: In conclusion, the authors observed a weak association between the APOE e4 allele and low-GFR cases and continuous GFR in non-Hispanic whites, and the APOE e2 allele and continuous GFR in non-Hispanic blacks, but found no association with either measure of kidney function in Mexican Americans. Larger studies including multiethnic groups are needed to determine the significance of this association.