RESUMO
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.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Creatinina , Nefropatias Diabéticas/genética , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Humanos , RimRESUMO
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.
Assuntos
Predisposição Genética para Doença , Taxa de Filtração Glomerular/genética , Rim/metabolismo , Insuficiência Renal Crônica/metabolismo , Biomarcadores , Creatinina/sangue , Cistatinas/farmacologia , Bases de Dados Genéticas , Europa (Continente) , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Rim/fisiologia , Especificidade de Órgãos , Locos de Características Quantitativas , RNA-Seq , Insuficiência Renal Crônica/genética , Fatores de Risco , Análise de Célula ÚnicaRESUMO
[Figure: see text].