The MDR1/ABCB1 gene, a high-impact risk factor for cardiac transplant rejection.
BACKGROUND
Variations in the expression and activity levels of the multidrug-resistance MDR1/ABCB1 encoded P- glycoprotein (P-gp) have an impact on the therapeutic efficacy of many drugs. C3435T and G2677 polymorphisms of the MDR1/ABCB1 gene correlate with cellular expression levels of P-gp, a membrane-bound efflux pump which removes a multitude of drugs, including chemotherapy drugs and immunosuppressants, from cells. We aimed to investigate whether the phenomenon of drug resistance, mediated by the MDR1/ABCB1 gene and seen in tumor cells to chemotherapeutic agents, is important in the field of transplantation, predisposing some patients to resistance to immunosuppressants.


METHODS
G2677 and C3435T polymorphisms of the ABCB1 gene were determined by PCR in 170 heart transplant recipients. We examined the relationship between MDR1/ABCB1 polymorphisms and endomyocardial biopsy-proven rejection (EBPR) determined by biopsy performed at set intervals according to a standard protocol.


RESULTS
A significant relationship was found between a patient's C3435T genotype and freedom from first grade > or =3A rejection episode. 3435-CC recipients were 1.8 times (1.05-3.09; P = 0.03) more likely to undergo a > or =3A rejection episode in the first 12 months. Haplotypes derived from the G2677 and C3435T polymorphisms (GG/CC, GT/CT and TT/TT) amplified this phenomenon further (log rank, P = 0.03; HR 2.18; 1.21-4.26; P = 0.02).


CONCLUSIONS
ABCB1 polymorphisms correlate with freedom from grade > or =3A EBPR and we believe that this may be attributed to MDR1/ABCB1 encoded P-gp mediating the efflux of immunosuppressants out of leukocytes, with depleted immunosuppressant levels in leukocytes manifesting as increased cellular rejection.
Barnard
James B
JB
The Transplant Centre, South Manchester University Hospitals NHS Trust, Manchester, United Kingdom. jamesbbarnard@doctors.org.uk
Richardson
Steven
S
Sheldon
Stephen
S
Fildes
James
J
Pravica
Vera
V
Hutchinson
Ian V
IV
Leonard
Colm T
CT
Yonan
Nizar
N
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D005091:Exons; D005260:Female; D006084:Graft Rejection / Q000235:genetics* / Q000473:pathology; D016027:Heart Transplantation / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters