Deceased donor multidrug resistance protein 1 and caveolin 1 gene variants may influence allograft survival in kidney transplantation
2015; Elsevier BV; Volume: 88; Issue: 3 Linguagem: Inglês
10.1038/ki.2015.105
ISSN1523-1755
AutoresJun Ma, Jasmin Divers, Nicholette D. Palmer, Bruce A. Julian, Ajay K. Israni, David P. Schladt, Stephen O. Pastan, Kryt Chattrabhuti, Michael D. Gautreaux, Věra Hauptfeld, Robert A. Bray, Allan D. Kirk, W. Mark Brown, Robert S. Gaston, Jeffrey Rogers, Alan C. Farney, Giuseppe Orlando, Robert J. Stratta, Meijian Guan, Amudha Palanisamy, Amber Reeves‐Daniel, Donald W. Bowden, Carl D. Langefeld, Andrew A. Hicks, Lijun Ma, Barry I. Freedman,
Tópico(s)Renal Transplantation Outcomes and Treatments
ResumoVariants in donor multidrug resistance protein 1 (ABCB1) and caveolin 1 (CAV1) genes are associated with renal allograft failure after transplantation in Europeans. Here we assessed transplantation outcomes of kidneys from 368 African American (AA) and 314 European American (EA) deceased donors based on 38 single-nucleotide polymorphisms (SNPs) spanning ABCB1 and 16 SNPs spanning CAV1, including previously associated index and haplotype-tagging SNPs. Tests for association with time to allograft failure were performed for the 1233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, panel reactive antibody, human leukocyte antigen match, expanded-criteria donation, and APOL1-nephropathy variants in AA donors. Interaction analyses between APOL1 with ABCB1 and CAV1 were performed. In a meta-analysis of all transplantations, ABCB1 index SNP rs1045642 was associated with time to allograft failure and other ABCB1 SNPs were nominally associated, but not CAV1 SNPs. ABCB1 SNP rs1045642 showed consistent effects with the 558 transplantations from EA donors, but not with the 675 transplantations from AA donors. ABCB1 SNP rs956825 and CAV1 SNP rs6466583 interacted with APOL1 in transplants from AA donors. Thus, the T allele at ABCB1 rs1045642 is associated with shorter renal allograft survival for kidneys from American donors. Interactions between ABCB1 and CAV1 with APOL1 may influence allograft failure for transplanted kidneys from AA donors. Variants in donor multidrug resistance protein 1 (ABCB1) and caveolin 1 (CAV1) genes are associated with renal allograft failure after transplantation in Europeans. Here we assessed transplantation outcomes of kidneys from 368 African American (AA) and 314 European American (EA) deceased donors based on 38 single-nucleotide polymorphisms (SNPs) spanning ABCB1 and 16 SNPs spanning CAV1, including previously associated index and haplotype-tagging SNPs. Tests for association with time to allograft failure were performed for the 1233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, panel reactive antibody, human leukocyte antigen match, expanded-criteria donation, and APOL1-nephropathy variants in AA donors. Interaction analyses between APOL1 with ABCB1 and CAV1 were performed. In a meta-analysis of all transplantations, ABCB1 index SNP rs1045642 was associated with time to allograft failure and other ABCB1 SNPs were nominally associated, but not CAV1 SNPs. ABCB1 SNP rs1045642 showed consistent effects with the 558 transplantations from EA donors, but not with the 675 transplantations from AA donors. ABCB1 SNP rs956825 and CAV1 SNP rs6466583 interacted with APOL1 in transplants from AA donors. Thus, the T allele at ABCB1 rs1045642 is associated with shorter renal allograft survival for kidneys from American donors. Interactions between ABCB1 and CAV1 with APOL1 may influence allograft failure for transplanted kidneys from AA donors. Genetic variations in organ donors and recipients have the potential to impact outcomes after transplantation.1.Gautreaux M.D. Freedman B.I. Genotypic variation and outcomes in kidney transplantation: donor and recipient effects.Kidney Int. 2013; 84: 431-433Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar In Europeans, variations in the donor multidrug resistance protein 1 (ABCB1) and caveolin 1 (CAV1) genes are associated with kidney allograft survival.2.Hauser I.A. Schaeffeler E. Gauer S. et al.ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation.J Am Soc Nephrol. 2005; 16: 1501-1511Crossref PubMed Scopus (193) Google Scholar, 3.Moore J. McKnight A.J. Simmonds M.J. et al.Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure.JAMA. 2010; 303: 1282-1287Crossref PubMed Scopus (65) Google Scholar, 4.Moore J. McKnight A.J. Dohler B. et al.Donor ABCB1 variant associates with increased risk for kidney allograft failure.J Am Soc Nephrol. 2012; 23: 1891-1899Crossref PubMed Scopus (62) Google Scholar, 5.DeMeyer M. Haufroid V. Elens L. et al.Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation.J Surg Res. 2012; 178: 988-995Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar In a similar manner, the G1 and G2 coding variants in the powerful apolipoprotein L1 gene (APOL1) have marked effects on time to renal allograft failure after transplantation from African American (AA) deceased donors,6.Reeves-Daniel A.M. Depalma J.A. Bleyer A.J. et al.The APOL1 gene and allograft survival after kidney transplantation.Am J Transplant. 2011; 11: 1025-1030Crossref PubMed Scopus (245) Google Scholar,7.Freedman B.I. Julian B.A. Pastan S.O. et al.Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.Am J Transplant. 2015https://doi.org/10.1111/ajt.13223Crossref Scopus (126) Google Scholar and variants in SHROOM3 predispose to renal allograft fibrosis.8.Menon M.C. Chuang P.Y. Li Z. et al.Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis.J Clin Invest. 2015; 125: 208-221Crossref PubMed Scopus (48) Google Scholar In contrast, variation in APOL1 in recipients of kidney transplants does not impact outcomes.9.Lee B.T. Kumar V. Williams T.A. et al.The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival.Am J Transplant. 2012; 12: 1924-1928Crossref PubMed Scopus (140) Google Scholar APOL1 G1 and G2 nephropathy-risk variants are virtually limited to populations with recent African ancestry. These variants produce ethnic-specific risk, as they are nearly absent in individuals with European, Hispanic, and Asian ancestry.10.Freedman B.I. Divers J. Palmer N.D. Population ancestry and genetic risk for diabetes and kidney, cardiovascular, and bone disease: modifiable environmental factors may produce the cures.Am J Kidney Dis. 2013; 62: 1165-1175Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar On the basis of the potential for ethnic-specific differences in risk allele frequencies, it is important to validate the effects of kidney-donor gene variants possibly affecting allograft survival in members of different racial/ethnic groups.11.Keaton J.M. Cooke Bailey J.N. Palmer N.D. et al.A comparison of type 2 diabetes risk allele load between African Americans and European Americans.Hum Genet. 2014; 133: 1487-1495Crossref PubMed Scopus (40) Google Scholar Assessment of variation along the full length of implicated genes is also required due to ancestry-specific haplotype block structures and to further refine the position of potential functional variants. Testing a single, previously associated, index genetic variant may be insufficient for full interrogation of effects of that gene on transplant outcomes in other ethnic groups. The present report assessed effects of variation in the ABCB1 and CAV1 genes of deceased European American (EA) and AA kidney donors on transplant outcomes. Haplotype-tagging single-nucleotide polymorphisms (htSNPs) spanning these genes were evaluated and genetic association analyses for time to renal allograft failure were performed for the resultant transplantations. Adjustment was done for the impact of APOL1 risk variants, and interactions between ABCB1 and CAV1 htSNPS with APOL1 were tested. The genetic association analyses for 675 kidney transplantations from AA donors were based on the results of two kidneys from the same donor separately engrafted in 102 Alabama and 205 North Carolina transplantations and one kidney engrafted from 17 Alabama and 44 North Carolina donors. Eight kidney transplantations were performed before 2001, 86 from 2001 to 2006, 397 from 2006 to 2010, and 184 after 2010. The median (first quartile, third quartile) follow-up duration after engraftment was 34.3 months (13.8, 57.9 months). Table 1 lists demographic characteristics of transplant recipients (57.8% of whom were African Americans) and of AA deceased organ donors. Median donor and recipient ages were 37.0 and 50.0 years, respectively; 59.2% of donors and 58.4% of recipients were male. Median terminal serum creatinine concentration was 1.1 mg/dl, peak panel reactive antibody (PRA) titer 5%, cold ischemia time 22.0 hours, and number of human leukocyte antigen (HLA) mismatches 5. Peak PRA titers exceeded 20% in 31.7, 34.1, and 31.9% of the recipients of Alabama AA, North Carolina AA, and North Carolina EA kidneys, respectively (P=0.71); induction immunosuppression was administered to 92.3, 89.7, and 92.7% of recipients of Alabama AA, North Carolina AA, and North Carolina EA kidneys, respectively (P=0.29).Table 1Demographic data for 368 African American kidney donors and 675 resultant transplantationsDonor characteristics (N=368)Categorical variablesN%Donor gender (% male)21859.2%Standard criteria donor (%)29680.4%Continuous variablesN1st QuartileMedianMeans.d.3rd QuartileDonor age (years)36820.037.035.317.550.0Donor terminal serum creatinine (mg/dl)3000.851.11.20.71.5Recipient characteristics (N=675)Categorical variablesN%Recipient gender (% male)39458.4%Recipient ethnicity (% African American)39057.8%Allograft failure (%)11717.3%Continuous variablesN1st QuartileMedianMeans.d.3rd QuartilePeak PRA (%)6740.05.023.832.838.0Recipient age (years)67538.050.047.815.660.0Recipient body mass index (kg/m2)62123.626.927.65.731.4Cold ischemia time (hours)64116.122.023.511.228.3HLA mismatch (#)6754.05.04.31.45.0Duration of transplant follow-up (months)67513.834.339.530.157.9Abbreviations: HLA, human leukocyte antigen; PRA, panel reactive antibody. Open table in a new tab Abbreviations: HLA, human leukocyte antigen; PRA, panel reactive antibody. The genetic association analyses for 558 kidney transplantations from EA donors were based on the results of two kidneys from the same donor separately engrafted in 244 North Carolina transplantations and one kidney engrafted from 70 North Carolina donors; 270 transplantations were performed from 2006 to 2010 and 288 after 2010. The median (first quartile, third quartile) follow-up duration after engraftment was 23.7 months (12.1, 33.9 months). Table 2 lists demographic characteristics of transplant recipients (42.3% of whom were African Americans) and of EA deceased organ donors. Median donor and recipient ages were 44.0 and 55.0 years, respectively; 60.5% of donors and 55.2% of recipients were male. Median terminal serum creatinine concentration was 0.9 mg/dl, peak PRA 6%, cold ischemia time 23.0 hours, and number of HLA mismatches 4. Immunosuppression varied by center, but generally included antibody induction with a calcineurin inhibitor (CNI) and an antiproliferative agent, with or without corticosteroids.Table 2Demographic data for 314 European American kidney donors and 558 resultant transplantationsDonor characteristics (N=314)Categorical variablesN%Donor gender (% male)19060.5%Standard criteria donor (%)23875.8%Continuous variablesN1st QuartileMedianMeans.d.3rd QuartileDonor age (years)31425.044.040.718.255.0Donor terminal serum creatinine (mg/dl)3140.70.91.21.41.4Recipient characteristics (N=558)Categorical variablesN%Recipient gender (% male)30855.2%Recipient ethnicity (% African American)23642.3%Allograft failure (%)478.4%Continuous variablesN1st QuartileMedianMeans.d.3rd QuartilePeak PRA (%)5550.06.023.432.940.0Recipient age (years)5586.055.052.615.164.0Recipient body mass index (kg/m2)54923.727.528.16.132.1Cold ischemia time (hours)54316.323.026.314.034.0HLA mismatch (#)5573.04.03.71.75.0Duration of transplant follow-up (months)55812.123.722.510.233.9Abbreviations: HLA, human leukocyte antigen; PRA, panel reactive antibody. Open table in a new tab Abbreviations: HLA, human leukocyte antigen; PRA, panel reactive antibody. In the meta-analysis of 1233 transplantations from all deceased AA and EA kidney donors, no SNPs in CAV1, including the previously associated index SNP rs4730751, met statistical significance for association with time to renal allograft failure in the fully adjusted model that accounted for donor APOL1 risk status in the AA subset and recipient, age, sex and ancestry (AA versus non-AA), HLA match, cold ischemia time, PRA level (0 vs. >0%), and expanded-criteria donor versus standard-criteria donor kidneys in AA and EA donors, Table 3. In contrast, the previously associated ABCB1 index SNP rs1045642 identified in European studies (hazard ratio (HR) 1.32, P=0.04, additive model) and five other ABCB1 htSNPs displayed nominal evidence of association; the 'T' allele in rs1045642 denoted risk for early allograft failure, opposing findings in the European report. The tested allele and the tested allele frequency for the EA subset in Table 3 corresponded to the minor allele in the AA subset. Only ABCB1 and CAV1 SNPs common to AA and EA donors, meeting quality control metrics and with sufficient counts with two copies of the minor allele, were analyzed in the meta-analysis. Thus, not all genotyped SNPs were included or shown in Table 3.Table 3Meta-analysis: ABCB1 and CAV1 single SNP associations with time to allograft failure in 1233 recipients of African American and European American donor kidneysGene – SNPPositionAfrican AmericanEuropean AmericanAdditive modelDominant modelRecessive modelMAMAFTATAFHRDirectionP-valueHRDirectionP-valueHRDirectionP-valueABCB1 rs1720983787495506C0.279C0.1550.92--0.730.92+-0.661.08-+0.84 rs105530287503600A0.303A0.1430.92--0.750.92+-0.641.05-+0.88 rs1706487504154T0.143T0.0690.86--0.530.86--0.480.98-+0.98 rs104564287509329T0.198T0.5161.32++0.041.32++0.121.79++0.03 rs1080807187511492G0.216G0.2070.65--0.010.65--0.020.43--0.15 rs694944887512498T0.226T0.4231.22++0.041.22++0.261.77++0.01 rs778708287527735G0.476G0.8291.00++0.431.00-+0.981.38++0.14 rs1023441187535576T0.241T0.4651.20++0.081.20++0.311.59++0.04 rs203258887550127T0.204T0.0610.84--0.520.84--0.371.30-+0.50 rs223502387561136A0.267A0.0670.96+-0.960.96+-0.821.14-+0.64 rs95682587562959A0.177A0.3100.98--0.420.98-+0.920.63--0.22 rs120216887566646T0.266T0.4351.43++0.011.43++0.041.59++0.04 rs695097887571151T0.122T0.2931.10+-0.771.10+-0.610.43--0.21 rs1026499087573299C0.200C0.3411.28+-0.431.28+-0.150.93+-0.88 rs120217987574963G0.423G0.3610.73--0.050.73--0.060.74--0.21 rs120218487584585A0.143A0.4981.34++0.061.34++0.141.42++0.21 rs120218287585988C0.316C0.3610.84--0.110.84--0.300.62--0.09 rs1732762487587501T0.180T0.2021.30+-0.121.30+-0.141.15+-0.74 rs218852687591246A0.154A0.4661.46++0.051.46++0.041.15-+0.63 rs378924387591570C0.441C0.4891.27++0.281.27++0.241.13-+0.56CAV1 rs4730748116527541G0.205G0.1880.71--0.320.71--0.071.62+-0.08 rs3807986116537771A0.444A0.7471.08+-0.811.08+-0.640.98+-0.93 rs4730751116540796A0.199A0.2800.99++0.810.99+-0.961.24++0.46 rs10270569116542728T0.224T0.2751.01++0.851.01+-0.941.11++0.73 rs11773845116551247A0.349A0.5550.88--0.230.88--0.500.76--0.24 rs729949116554851A0.336A0.2811.12-+0.421.12-+0.511.07-+0.79 rs3807992116557191A0.367A0.2771.10-+0.541.10-+0.570.96-+0.86 rs8713116559743C0.282C0.1891.07-+0.881.07-+0.690.87-+0.68 rs2052106116566611G0.386G0.6670.98--0.630.98+-0.900.85-+0.52Abbreviations: HR, hazard ratio; MA, minor allele; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; TA, tested allele; TAF, tested allele frequency. ABCB1 and CAV1 haplotype-tagging SNPs common to African American and European American donors, meeting quality control metrics, and with sufficient counts with two copies of the minor allele are included. Open table in a new tab Abbreviations: HR, hazard ratio; MA, minor allele; MAF, minor allele frequency; SNP, single-nucleotide polymorphism; TA, tested allele; TAF, tested allele frequency. ABCB1 and CAV1 haplotype-tagging SNPs common to African American and European American donors, meeting quality control metrics, and with sufficient counts with two copies of the minor allele are included. Association analyses for time to allograft failure limited to recipients of AA donor kidneys are shown in Supplementary Table S2 online. Results are presented in fully adjusted models as above, with additional adjustment for donor APOL1 risk (recessive). Three of the 38 ABCB1 SNPs were nominally associated with time to allograft failure (additive models): rs10808071 (HR 0.68, P=0.045), rs10264990 (HR 1.53, P=0.019), and rs17327624 (HR 1.50, P=0.02). The ABCB1 SNP rs1045642 was not associated with allograft failure. Supplementary Table S2 online shows that only one of 16 CAV1 htSNPs was nominally associated with time to allograft failure: rs4730748 (HR 1.97, P=0.03 recessive model). Additional adjustments for recipient diabetic kidney disease and donor age did not alter association results in the meta-analysis or the analyses within each race group (data not shown). Download .pdf (3.27 MB) Help with pdf files Supplementary Materials Association results for time to allograft failure in recipients of EA donor kidneys are presented in Supplementary Table S3 online. Three of 32 ABCB1 SNPs were nominally associated with time to kidney allograft failure (additive models): index SNP rs1045642 (HR 0.66, P=0.04), rs6949448 (HR 1.52, P=0.04), rs2235046 (HR 1.47, P=0.05).4.Moore J. McKnight A.J. Dohler B. et al.Donor ABCB1 variant associates with increased risk for kidney allograft failure.J Am Soc Nephrol. 2012; 23: 1891-1899Crossref PubMed Scopus (62) Google Scholar Among 14 CAV1 htSNPs, rs3807992 (HR 1.54, P=0.03, additive model) and rs9920 (HR 1.92, P=0.01, additive model) were nominally associated with time to allograft failure. We performed immunostaining of ABCB1 and CAV1 proteins in non-diseased human kidney cryosections to confirm their presence in renal cells and determine whether APOL1 interaction analyses might be clinically relevant. APOL1 protein localization in kidney tissue has been reported, with high levels (and cellular uptake) in podocytes; lower APOL1 protein levels are seen in renal tubular cells and glomerular endothelial cells, and APOL1 protein and mRNA are absent in mesangial cells.12.Ma L. Shelness G.S. Snipes J.A. et al.Localization of APOL1 Protein and mRNA in the human kidney: nondiseased tissue, primary cells, and immortalized cell lines.J Am Soc Nephrol. 2014; 26: 339-348Crossref PubMed Scopus (97) Google Scholar In the current analyses, robust ABCB1 fluorescence was observed in mesangial cells and smooth muscle cells of renal arterioles; ABCB1 was also present in endothelial cells in glomeruli and medium-sized renal arterioles. Although ABCB1 fluorescence was observed in renal tubule cells, it was considerably less intense than the staining in mesangial cells (Supplementary Figures S1–S5 online). CAV1 was present in mesangial cells, smooth muscle cells in renal arterioles, and endothelial cells of glomeruli and medium-sized renal arterioles (Supplementary Figures S6–S9 online). CAV1 was not enriched in proximal tubule cells or podocytes (Supplementary Figures S10 and S11 online). Fluorescence of low intensity for ABCB1 and higher intensity for APOL1 proteins in renal tubule cells, coupled with CAV1 and APOL1 proteins in glomerular endothelial cells and arteriolar cells, supported performance of gene–gene interaction analyses on renal transplantation outcomes. Low levels of ABCB1 expression in tubules may amplify the toxicity of APOL1 G1/G2 nephropathy-risk variants on CNI treatment after kidney transplantation. Table 4 displays results of testing for genetic interaction between ABCB1 and CAV1 SNPs with the powerful APOL1 G1 and G2 nephropathy-risk variants in transplantation of allografts from AA donors. The recessive model was used to define APOL1-mediated risk.13.Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1408) Google Scholar Significant interaction effects with APOL1 were observed for ABCB1 htSNP rs956825 (P=0.001; dominant model) and CAV1 htSNP rs6466583 (P=0.004; recessive model), revealing potentially important gene–gene interactions on time to renal allograft survival (Figures 1 and 2).Table 4Interaction analysis of APOL1 nephropathy-risk variants (recessive) with ABCB1 and CAV1 on time to allograft failure in recipients of African American donor kidneysGeneSNPFully adjusted modelHRs.e.P-valueHRs.e.P-valueHRs.e.P-valueAdditive modelDominant modelRecessive modelABCB1rs172098371.840.510.231.630.520.357.851.060.05rs69461190.560.830.490.540.870.48NA0.00NArs10553021.570.480.351.430.530.494.201.110.20rs170642.650.530.062.200.540.14NA0.67NArs22350471.240.440.631.340.550.59NA0.88NArs10456422.460.500.072.810.520.05NA0.00NArs108080710.270.600.030.260.620.030.001.27NArs171496992.420.450.052.360.530.116.951.200.11rs69494480.980.400.960.900.540.841.440.530.50rs41487494.150.660.034.190.690.04NA0.00NArs77795622.250.430.062.320.570.144.140.710.05rs23735891.070.360.861.560.560.430.361.060.34rs4148740NA0.00NANA0.00NANA0.00NArs77870820.790.480.610.670.550.470.810.760.79rs102745870.570.550.310.530.620.310.001.27NArs102344110.920.410.830.820.530.711.430.500.47rs22350411.050.590.940.750.810.73NA1.30NArs37892461.660.530.341.510.560.46NA0.00NArs12720066NA0.00NANA0.00NANA0.00NArs20325880.750.500.570.680.560.491.180.970.86rs22350230.550.450.180.450.530.140.690.960.70rs9568254.550.470.005.000.560.009.431.130.05rs12021681.280.360.501.470.520.461.100.590.88rs69509782.470.590.132.390.600.15NA0.00NArs102649900.850.550.770.800.570.69NA0.00NArs12021790.620.320.140.660.540.440.290.680.07rs132267261.520.690.552.311.390.552.311.390.55rs47287051.460.830.651.370.830.70NA0.00NArs12021841.300.520.611.390.530.54NA0.00NArs1211152NA0.00NANA0.00NANA0.00NArs12021820.470.360.040.350.550.060.380.710.17rs173276241.140.430.761.040.510.942.331.030.41rs21885261.270.350.491.650.510.331.521.040.68rs37892431.230.350.561.230.550.711.480.640.54rs22141040.291.220.310.311.230.34NA0.00NArs21579281.460.590.521.170.570.79NA0.00NArs10154151.360.700.661.440.700.61NA0.00NArs69720981.020.400.961.230.520.700.451.160.49CAV1rs9750282.450.460.052.690.530.060.571.280.66rs47307480.420.660.180.520.680.33NA0.00NArs64665832.370.360.022.220.710.274.490.530.004rs38079860.550.430.160.350.540.060.670.910.67rs47307510.800.650.730.670.690.562.841.480.48rs102705690.760.600.640.600.620.413.581.480.39rs37795142.090.320.023.750.540.010.820.510.69rs117738450.710.430.420.540.570.270.860.860.86rs7299490.570.400.160.490.520.170.520.830.43rs38079920.680.370.290.660.520.420.470.780.34rs87130.790.480.630.670.550.471.471.220.75rs99204.371.080.172.561.500.53NA0.00NArs171388120.570.630.370.630.870.60NA1.00NArs119740880.610.700.480.650.700.54NA2.00NArs20521060.720.430.450.540.560.270.950.840.95Abbreviations: HR, hazard ratio; NA, not applicable due to low minor allele frequency counts; SNP, single-nucleotide polymorphism. Open table in a new tab Figure 2Kaplan–Meier plots with time to allograft failure based on the significant interaction (P=0.004, recessive model) between APOL1 risk variants (recessive; APOL1=2 signifies risk) and CAV1 haplotype-tagging single-nucleotide polymorphism rs6466583 (rs6466583=2 signifies risk).View Large Image Figure ViewerDownload (PPT) Abbreviations: HR, hazard ratio; NA, not applicable due to low minor allele frequency counts; SNP, single-nucleotide polymorphism. In silico prediction softwares (SIFT/Polyphen) are not available for potential effects of non-coding SNPs. RegulomeDB, a tool that queries multiple data resources and annotates SNPs with respect to known and predicted regulatory elements, including DNAase hypersensitivity, transcription factor binding sites and promoter regions, in intergenic regions, was explored. Among the six SNPs associated in the meta-analysis (Table 3), the following scores returned: rs1045642 (synonymous), rs10808071 (3a), rs6949448 (7), rs1202168 (5), rs1202179 (2b), and rs2188526 (5), where lower scores indicate increased support from multiple data sets. The scores returned in this analysis were not exceedingly strong (e.g., rs1202179 was assigned a score of 2b, which can be interpreted as support from four of nine resources). This is not surprising as htSNPs variants were chosen to capture variation, as opposed to functional implications. This is the first report evaluating common genetic variation in CAV1 and ABCB1 in American deceased organ donors for impact on time to allograft failure after kidney transplantation. ABCB1 index SNP rs1045642 was selected, as it was putatively functional and associated with renal allograft survival in a European report; 37 additional ABCB1 htSNPs were selected to comprehensively assess common variation. In American deceased kidney donors, rs1045642 revealed an effect on time to allograft failure in the same direction as reports of genetic risk for CNI toxicity. However, the direction of these associations opposed that reported in Europeans for time to renal allograft failure. Variation in CAV1 did not significantly affect transplant outcomes from the meta-analysis of AA and EA donors.2.Hauser I.A. Schaeffeler E. Gauer S. et al.ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation.J Am Soc Nephrol. 2005; 16: 1501-1511Crossref PubMed Scopus (193) Google Scholar, 3.Moore J. McKnight A.J. Simmonds M.J. et al.Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure.JAMA. 2010; 303: 1282-1287Crossref PubMed Scopus (65) Google Scholar, 4.Moore J. McKnight A.J. Dohler B. et al.Donor ABCB1 variant associates with increased risk for kidney allograft failure.J Am Soc Nephrol. 2012; 23: 1891-1899Crossref PubMed Scopus (62) Google Scholar In addition, SNPs in ABCB1 and in CAV1 appeared to interact with donor APOL1 nephropathy-risk variants to impact time to allograft failure in kidneys transplanted from deceased AA donors. These analyses comprise the first APOL1-second gene interaction analyses performed in kidney transplantation. ABCB1 is important to evaluate in American deceased kidney donors, particularly African Americans, on the basis of the results of association studies in Europeans and given the role of the ABCB1 protein in transporting CNIs from cells and preventing intracellular accumulation with potential for tubulointerstitial kidney disease.14.Fakata K.L. Elmquist W.F. Swanson S.A. et al.Cyclosporin A has low potency as a calcineurin inhibitor in cells expressing high levels of P-glycoprotein.Life Sci. 1998; 62: 2441-2448Crossref PubMed Scopus (11) Google Scholar,15.Joy M.S. Nickeleit V. Hogan S.L. et al.Calcineurin inhibitor-induced nephrotoxicity and renal expression of P-glycoprotein.Pharmacotherapy. 2005; 25: 779-789Crossref PubMed Scopus (47) Google Scholar The present report thoroughly interrogated common variation in CAV1 and ABCB1 via a haplotype-tagging approach. The previously identified and putatively functional ABCB1 index variant rs1045642 showed association with time to renal allograft failure in kidneys donated by EAs (Supplementary Table S3 online) and in the meta-analysis of transplantations from AA and EA donors (Table 3), but in the opposite direction of the European report (no association was seen in analyses limited to transplantations from AA donors; Supplementary Table S2 online). Although the 'T' allele in rs1045642 (C3435T) denoted risk for early allograft failure in our report, versus longer allograft survival in the European report,4.Moore J. McKnight A.J. Dohler B. et al.Donor ABCB1 variant associates with increased risk for kidney allograft failure.J Am Soc Nephrol. 2012; 23: 1891-1899Crossref PubMed Scopus (62) Google Scholar the TT genotype is reported to reduce p-gp renal expression.16.Kimchi-Sarfaty C. Oh J.M. Kim I.W. et al.A "silent" polymorphism in the MDR1 gene changes substrate specificity.Science. 2007; 315: 525-528Crossref PubMed Scopus (2004) Google Scholar This effect should enhance risk for CNI toxicity. Consistent with our findings, reports in independent French, Belgian and German studies reveal that the rs1045642 T allele in donor kidneys was associated with risk of CNI nephropathy/renal allograft injury.2.Hauser I.A. Schaeffeler E. Gauer S. et al.ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation.J Am Soc Nephrol. 2005; 16: 1501-1511Crossref PubMed Scopus (193) Google Scholar, 17.Naesens M. Lerut E. de J.H. et al.Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts.J Am Soc Nephrol. 2009; 20: 2468-2480Crossref PubMed Scopus (114) Google Scholar, 18.Woillard J.B. Rerolle J.P. Picard N. et al.Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up.Clin Pharmacol Ther. 2010; 88: 95-100Crossref PubMed Scopus (58) Google Scholar It is possible that these controversial results for ABCB1 SNP rs1045642 in these reports, compared with the European study,4.Moore J. McKnight A.J. Dohler B. et al.Donor ABCB1 variant associates with increased risk for kidney allograft failure.J Am Soc Nephrol. 2012; 23: 1891-1899Crossref PubMed
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