Journal List > J Korean Soc Transplant > v.27(3) > 1034396

Ro, Min, Jeong, Koo, Yang, Ha, and Ahn: The Impact of ABCB1 Gene Polymorphism on Steroid Responsiveness in Acute Rejection in Kidney Transplantation

Abstract

Background:

Steroid pulse therapy has been used for patients with acute rejection after kidney transplantation. The ABCB1 gene codes for P-glycoprotein, a transporter that is involved in the metabolism of steroids. However, the role of ABCB1 polymorphisms has not been investigated in patients with acute rejection after kidney transplantation.

Methods:

Among 763 patients that received kidney or simultaneous pancreas-kidney transplantation at Seoul National University Hospital between May 1996 and July 2009, 684 patients agreed to genetic sampling for polymorphisms. Acute rejection was defined as biopsy-proven, acute cellular rejection with increased serum creatinine, or in the context of delayed or slow graft function. Steroid-resistance was defined as no improvement in serum creatinine, need for additional OKT3 or ATG treatment, or repeated acute rejection within 30 days. Three polymorphisms of ABCB1 gene (C1236T, C3435T, G2677T/A) were assessed.

Results:

C allele frequency of C3435T was 59.3% and of C1236T 40.1%. Patients who were steroid-resistant (n=37) had higher serum creatinine at kidney biopsy compared to those who were steroid-sensitive (n=49, P<0.001). The frequency of ABCB1 gene polymorphisms (C1236T and C3435T) did not differ significantly between patients who were steroid-sensitive and those who were resistant. An association with G2677T/A could not be analyzed due to a high failure rate of genotyping.

Conclusions:

ABCB1 gene polymorphisms (C1236T and C3435T) were not associated with steroid resistance in patients with acute cellular rejection after kidney transplantation.

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Table 1.
Distribution of ABCB1 single nucleotide polymorphisms
  Present study Healthy control
Previous study Hapmap data
Genotype Patients (n=86) HWE (P value) Korean a (n=100) Indian b (n=216) European (n=226) Chinese (n=84) Japanese (n=172)
C3435T C 59.3 0.58 58.5 50.5 42.9 58.3 54.1
  T 40.7   41.5 49.5 57.1 45.9 45.9
C1236T C 40.1 0.41 35.5 67.4 54.8 29.1 41.3
  T 59.9   64.5 32.6 45.1 70.9 58.7
G2677T/A G 52.7 Genotyping 37.0 72.7 38.4 53.1 44.8
  T 33.9 failure (n=30) 43.0 27.3 61.6 46.9 55.2
  A 13.4   20.0 - - - -

Data are presented as percentage.

Abbreviation: HWE, Hardy-Weinberg equilibrium.

a Korean healthy control (reference 14);

b Indian healthy control (reference 30).

Table 2.
Comparison of baseline characteristics according to steroid resistance
Characteristic Steroid-sensitive (group 1, n=49) Steroid-resistant (group 2, n=37) P value
Recipient age ≥18 yr 36 31 0.254
Recipient gender, male 32 23 0.764
Donor type (living:deceased) 43:6 32:5 1.000
Diabetes mellitus of recipient 9 3 0.174
Preemptive transplantation 6 5 1.000
HLA mismatch 3.34±1.52 2.84±1.71 0.158
Retransplantation 0 1 0.430
Induction therapy 30 19 0.360
Simultaneous pancreas kidney transplantation 6 2 0.457
Serum creatinine at steroid pulse therapy (mg/dL) 2.02±1.05 3.72±3.75 <0.001
Duration to acute rejection (day) 323±785 557±912 0.206

Data are presented as mean±SD.

Abbreviation: HLA, human leukocyte antigen.

Table 3.
Association of ABCB1 genotypes with steroid resistant rejection episodes
SNPs   SS (n=49) SR (n=37) OR (95% CI) P value
ABCB1 C1236T TT 20 (40.8) 9 (24.9) 1 (reference)  
  TC 21 (42.9) 24 (64.9) 2.540 (0.952∼6.772) 0.063
  CC 8 (16.3) 4 (10.8) 1.111 (0.265∼4.667) 0.886
  T allele 62.2 56.8 1 (reference)  
  C allele 37.8 43.2 1.256 (0.679∼2.324) 0.467
ABCB1 C3435T CC 15 (30.6) 14 (37.8) 1 (reference)  
  CT 24 (49.0) 20 (54.1) 0.893 (0.349∼2.285) 0.813
  TT 10 (20.4) 3 (8.1) 0.321 (0.073∼1.414) 0.133
  C allele 55.1 64.9 1 (reference)  
  T allele 44.9 35.1 0.665 (0.357∼1.238) 0.197

Data are presented as number (%) or percentage.

Abbreviations: SNP, single nucleotide polymorphism; SS, steroid-sensitive; SR, steroid-resistant; OR, odds ratio; CI, confidence interval.

Table 4.
Comparison of baseline characteristics according to steroid resistance (excluding delayed graft function/slow graft function status)
Characteristic Steroid-sensitive (group 3, n=36) Steroid-resistant (group 4, n=24) P value
Recipient age ≥18 yr 23 19 0.206
Recipient gender, male 25 14 0.377
Donor type (living:deceased) 33:3 24:0 0.268
Diabetes mellitus of recipient 8 3 0.500
Preemptive transplantation 5 4 1.000
HLA mismatch 3.24±1.50 2.33±1.40 0.024
Retransplantation 0 1 0.400
Induction therapy 20 8 0.091
Simultaneous pancreas kidney transplantation 5 2 0.691
Serum creatinine at steroid pulse therapy (mg/dL) 1.80±0.55 4.45±4.32 <0.001
Duration to acute rejection (day) 436±892 854±1,019 0.099

Data are presented as mean±SD.

Abbreviation: HLA, human leukocyte antigen.

Table 5.
Association of ABCB1 genotypes with steroid resistant rejection episodes (excluding delayed graft function/slow graft function status)
SNPs   SS (n=36) SR (n=24) OR (95% CI) P value
ABCB1 C1236T TT 16 (44.4) 6 (25.0) 1 (reference)  
  TC 16 (44.4) 15 (62.5) 2.500 (0.773∼8.081) 0.126
  CC 4 (11.1) 3 (12.5) 2.000 (0.342∼11.703) 0.442
  T allele 66.7 56.3 1 (reference)  
  C allele 33.3 43.8 1.556 (0.733∼3.299) 0.248
ABCB1 C3435T CC 10 (27.8) 7 (29.2) 1 (reference)  
  CT 17 (47.2) 14 (58.3) 1.176 (0.355∼3.895) 0.790
  TT 9 (25.0) 3 (12.5) 0.476 (0.094∼2.418) 0.371
  C allele 51.4 58.3 1 (reference)  
  T allele 48.6 41.7 0.755 (0.361∼1.578) 0.454

Data are presented as number (%) or percentage.

Abbreviations: SNP, single nucleotide polymorphism; SS, steroid-sensitive; SR, steroid-resistant; OR, odds ratio; CI, confidence interval.

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