Multiple loci associated with indices of renal function and chronic kidney disease

Abstract

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity.1 We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate estimated by serum creatinine (eGFRcrea), cystatin C (eGFRcys), and CKD (eGFRcrea<60 ml/min/1.73m2) in European-ancestry participants of four populations-based cohorts (ARIC, CHS, FHS, RS; n=19,877, 2,388 CKD cases), and tested for external replication in 21,466 participants (1,932 CKD cases). Significant associations (p<5*10−8) were identified for SNPs with [1] CKD at the UMOD locus; [2] eGFRcrea at the UMOD, SHROOM3, and GATM/SPATA5L1 loci; [3] eGFRcys at the CST and STC1 loci. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein,2 and rare mutations in UMOD cause Mendelian forms of kidney disease.3 Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

“…When compared to other traits (digestive, nervous, immune system diseases, cardiovascular, body measurement, biological processes, and other diseases), we found a significantly greater overlap between kidney eSNPs and polymorphisms that are associated with kidney function. 13,16,17,54 These results indicate that genetic variants associated with kidney function and CKD are enriched in our eQTL studies and likely drive gene expression changes in the kidney.…”

“…We manually curated a list of SNPs that both passed genome-wide significance and were associated with kidney disease traits (Table S7). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] To acquire independent loci, we removed any SNPs having r 2 R 0.2. In total, we analyzed 110 leading SNPs and 2,357 tagging SNPs with r 2 R 0.8 (Table S7).…”

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“…Defects in UMOD gene are linked to the autosomal dominant renal disorders medullary cystic kidney disease-2 (MCKD2) and familial juvenile hyperuricemia nephropathy (FJHN) [16]. Rare mutations in UMOD cause mendelian forms of kidney disease [14]. Therefore, our objective of this study was to detect the possible mutation in this UMOD gene among Saudi patients with renal failure.…”

“…The human UMOD gene is located on chromosome 16 and encodes the most common protein in human urine, Tamm-Horsfall protein (THP). Uromodulin is a glycoprotein that is encoded by the UMOD gene [13,14]. Uromodulin is the most plentiful protein expelled in familiar urine [15].…”

Uromodulin Levels in Chronic Kidney Disease

“…[2] In addition, the emerging epidemiologic evidence by genome wide association study that Uromodulin polymorphism may be associated with the development of end-stage renal disease (ESRD) regardless of the specific diagnosis also compels to study its trend in CKD. [3] Uromodulin, also known as Tamm-Horsfall protein (THP), was first described by Tamm and Horsfall in 1950 as a urinary mucoprotein that is able to inhibit viral agglutination [4]. Subsequently it has been also linked to water electrolyte balance, protective role against urinary tract infections and renal stone formation [5].…”