Association of ABCB1 genetic variants with renal function in Africans and in Caucasians

Abstract

Background: 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. We investigated the association of ABCB1 variants with renal function in African and Caucasian subjects.

Methods: In 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.

Results: In 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).

Conclusion: Variants 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.

Figure 1

Renal haemodynamics by genotypes for each ABCB1 variant. Bar heights are means and vertical lines standard errors. P: P value for linear trend across genotypes using the ASSOC program in S.A.G.E. in models without additional covariates. GFR: glomerular filtration rate measured using inulin clearance. ERPF: effective renal plasma flow measured using PAH clearance. RVR: renal vascular resistance.

Figure 2

Renal haemodynamics by hypertension status for the 2677 C>T ABCB1 variants. Bar heights are means and vertical lines standard errors. P: P value for linear trend across genotypes using the ASSOC program in S.A.G.E. in models without additional covariates. GFR: glomerular filtration rate measured using inulin clearance. ERPF: effective renal plasma flow measured using PAH clearance. RVR: renal vascular resistance.

Figure 3

Genetic associations with GFR, in the region around the ABCB1 gene. Associations are shown for both directly genotyped and imputed SNPs. The bottom panel shows the pattern of linkage disequilibrium in the HapMap CEU panel. We imputed genotypes for all HapMap SNPs in the region around ABCB1. In this region, linkage disequilibrium patterns in CoLaus were similar to the ones observed in HapMap, although they were resolved at a coarser scale due to lower SNP density. Since it was not computationally feasible to combine imputation and permutation approaches, we plot P values calculated assuming the normal linear model. For directly genotyped SNPs, the differences between calculated and permutation P values were small. The top three hits (and P values) are rs17327624 (0.0006), rs4148733 (0.0008) and rs17327442 (0.0008). The former two were directly genotyped and are in strong LD (D' = 0.96 in CoLaus and 1.00 in HapMap CEU, r² = 0.63 and 0.72 respectively), and the imputed SNP rs17327442 is in perfect LD with rs17327624 in HapMap CEU.