Abstract
BackgroundThe P-glycoprotein, encoded by the ABCB1 gene, is expressed in human endothelial and mesangial cells, which contribute to control renal plasma flow and glomerular filtration rate. We investigated the association of ABCB1 variants with renal function in African and Caucasian subjects.MethodsIn Africans (290 subjects from 62 pedigrees), we genotyped the 2677G>T and 3435 C>T ABCB1 polymorphisms. Glomerular filtration rate (GFR) was measured using inulin clearance and effective renal plasma flow (ERPF) using para-aminohippurate clearance. In Caucasians (5382 unrelated subjects), we analyzed 30 SNPs located within and around ABCB1, using data from the Affymetrix 500 K chip. GFR was estimated using the simplified Modification of the Diet in Renal Disease (MDRD) and Cockcroft-Gault equations.ResultsIn Africans, compared to the reference genotype (GG or CC), each copy of the 2677T and 3435T allele was associated, respectively, with: GFR higher by 10.6 ± 2.9 (P < 0.001) and 4.4 ± 2.3 (P = 0.06) mL/min; ERPF higher by 47.5 ± 11.6 (P < 0.001) and 28.1 ± 10.5 (P = 0.007) mL/min; and renal resistances lower by 0.016 ± 0.004 (P < 0.001) and 0.011 ± 0.004 (P = 0.004) mm Hg/mL/min. In Caucasians, we identified 3 polymorphisms in the ABCB1 gene that were strongly associated with all estimates of GFR (smallest P value = 0.0006, overall P = 0.014 after multiple testing correction).ConclusionVariants of the ABCB1 gene were associated with renal function in both Africans and Caucasians and may therefore confer susceptibility to nephropathy in humans. If confirmed in other studies, these results point toward a new candidate gene for nephropathy in humans.
Highlights
The P-glycoprotein, encoded by the ABCB1 gene, is expressed in human endothelial and mesangial cells, which contribute to control renal plasma flow and glomerular filtration rate
PGP is widely expressed in the human kidney [5,6,7] and is involved in ciclosporininduced post-transplantation nephrotoxicity [5,8,9], possibly because of its influence on ciclosporin absorption. [10]ABCB1 genetic variants have been associated with post-transplantation ciclosporin-induced nephrotoxicity. [10,11,12] In contrast to the extensive data about the physiological role of PGP on the transport of xenobiotics, little is known about the role of PGP in the transport of endogenous substrates and to our knowledge, ABCB1 gene variants have not been previously associated with renal function in the absence of xenobiotics in humans. [13]
We investigated whether the 3435 C>T and the 2677G>T ABCB1 variants are associated with Glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and renal vascular resistance (RVR) in families of African descent
Summary
The P-glycoprotein, encoded by the ABCB1 gene, is expressed in human endothelial and mesangial cells, which contribute to control renal plasma flow and glomerular filtration rate. The transmembrane efflux-P-glycoprotein (PGP; known as multidrug resistance-associated protein 1) is encoded by the ABCB1 gene, several genetic variants of which have been shown to influence PGP expression in humans. PGP is widely expressed in the human kidney [5,6,7] and is involved in ciclosporininduced post-transplantation nephrotoxicity [5,8,9], possibly because of its influence on ciclosporin absorption. [10,11,12] In contrast to the extensive data about the physiological role of PGP on the transport of xenobiotics, little is known about the role of PGP in the transport of endogenous substrates and to our knowledge, ABCB1 gene variants have not been previously associated with renal function in the absence of xenobiotics in humans. PGP is widely expressed in the human kidney [5,6,7] and is involved in ciclosporininduced post-transplantation nephrotoxicity [5,8,9], possibly because of its influence on ciclosporin absorption. [10]ABCB1 genetic variants have been associated with post-transplantation ciclosporin-induced nephrotoxicity. [10,11,12] In contrast to the extensive data about the physiological role of PGP on the transport of xenobiotics, little is known about the role of PGP in the transport of endogenous substrates and to our knowledge, ABCB1 gene variants have not been previously associated with renal function in the absence of xenobiotics in humans. [13]
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