Genome-wide signi fi cant locus of beta-trace protein , a novel kidney function biomarker , identi fi ed in European and African Americans

Background. Beta-trace protein (BTP), measured in serum or plasma, has potential as a novel biomarker for kidney function. Little is known about the genes influencing BTP levels. Methods. We conducted a genome-wide association study of log-transformed plasma BTP levels in 6720 European Americans (EAs) and replicated the significant associations in 1734 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC) study. Results. We identified a genome-wide significant locus in EA upstream of Prostaglandin D2 synthase (PTGDS), the gene encoding BTP. Each copy of the A allele at rs57024841 was associated with 5% higher BTP levels (P = 1.2 × 10). The association at PTGDS was confirmed in AAs (6% higher BTP for each A allele at rs57024841, P = 1.9 × 10). The index single nucleotide polymorphisms (SNPs) in EAs and AAs explained ∼1.1% of the log(BTP) variance within each population and explained over 30% of the difference in log(BTP) levels between EAs and AAs. The index SNPs at the PTGDS locus in the two populations were not associated with the estimated glomerular filtration rate (eGFR) or the urine albumin creatinine ratio (P > 0.05). We further tested for the associations of BTP with 16 known loci of the eGFR in EA, and BTP was associated with 3 of 16 tested. Conclusions. The identification of a novel BTP-specific (nonrenal related) locus and the confirmation of several genetic loci of the eGFR with BTP extend our understanding of the metabolism of BTP and inform its use as a kidney filtration biomarker. INTRODUCTION The glomerular filtration rate (GFR) is the most widely accepted index of kidney function. The direct measure of the GFR using an exogenous molecule is an invasive procedure and often impractical in both clinical and research settings [1]. Therefore, it is often estimated using equations based on endogenous biomarker levels, such as serum creatinine (SCr). Discovery and characterization of novel filtration markers, such as beta-trace protein (BTP) and cystatin C, are important for improving the precision and reducing bias in GFR estimation due to non-GFR factors influencing SCr [2]. However, novel filtration markers will have their own non-GFR factors. Advances in human genetics are enabling an unbiased characterization of common genetic variation influencing any novel filtration biomarker. BTP, measured in serum or plasma, has been found to be more sensitive than SCr in detecting a modest decline in the GFR [3–6]. BTP is a low-molecular weight protein (23–29 kDa) that is freely filtered by the kidney. It has been shown to be associated with risk of kidney failure and mortality in participants with chronic kidney disease (CKD) in the Modification of Diet in Renal Disease and African American Study of Kidney Disease and Hypertension studies [7] and with risk of end-stage renal disease (ESRD) in African Americans (AAs) having hypertensive CKD after controlling for measured GFR [8]. Recently, the Atherosclerosis Risk in Communities (ARIC) population-based cohort also found BTP to have O R IG IN A L A R T IC L E © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 1497 D ow naded rom http/academ ic.p.com /ndt/article-at/28/6/1497/1837717 by gest on 14 Feruary 2019 stronger associations with ESRD, cardiovascular disease and mortality than SCr estimates of the GFR [9]. Little is known about with non-kidney-related factors influencing BTP levels. The primary goal of this study was to identify genetic loci of BTP. As a biomarker of kidney function, BTP may be associated with kidney function loci or loci specific to the regulation of BTP. Our secondary goal was to examine the association between BTP and known eGFR loci. Investigation into the genetic associations of BTP can enhance our understanding of the biological mechanisms underlying BTP metabolism and inform its potential use as a kidney function biomarker. We conducted a genome-wide association study (GWAS) of plasma BTP in a large population-based cohort, tested replication of the genome-wide significant results, determined whether this locus was associated with kidney function and finally tested for the associations of BTP with 16 previously identified GFR loci among individuals of European ancestry [10].