Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles.
We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.
University of Minnesota, Experimental and Clinical Pharmacology, Minneapolis, MN.
W S
WS
Oetting
Minneapolis Medical Research Foundation, Minneapolis, MN.
D P
DP
Schladt
University of Minnesota, Department of Biostatistics, Minneapolis, MN.
W
W
Guan
University of Minnesota, Experimental and Clinical Pharmacology, Minneapolis, MN.
M B
MB
Miller
University of Minnesota, Experimental and Clinical Pharmacology, Minneapolis, MN.
R P
RP
Remmel
Minneapolis Medical Research Foundation, Minneapolis, MN.
C
C
Dorr
University of Minnesota, Experimental and Clinical Pharmacology, Minneapolis, MN.
K
K
Sanghavi
University of Alabama, Division of Nephrology, Birmingham, AL.
R B
RB
Mannon
University of California, San Francisco, CA.
B
B
Herrera
University of Minnesota, Department of Surgery, Minneapolis, MN.
A J
AJ
Matas
The Scripps Research Institute, La Jolla, CA.
D R
DR
Salomon
University of California, San Francisco, CA.
P-Y
PY
Kwok
Children's Hospital of Philadelphia, Philadelphia, PA.
B J
BJ
Keating
Minneapolis Medical Research Foundation, Minneapolis, MN.|University of Minnesota, Department of Medicine, Hennepin County Medical Center, Minneapolis, MN.|University of Minnesota, Department of Epidemiology and Community Health, Minneapolis, MN.
A K
AK
Israni
University of Minnesota, Experimental and Clinical Pharmacology, Minneapolis, MN.
P A
PA
Jacobson
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D005838:Genotype; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011183:Postoperative Complications / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D016559:Tacrolimus / Q000627:therapeutic use*; D014019:Tissue Donors; D066027:Transplant Recipients; D044465:White People / Q000235:genetics; D055815:Young Adult
D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
basic (laboratory) research/science; genetics; genomics; immunosuppressant; calcineurin inhibitor: tacrolimus; immunosuppression/immune modulation; microarray/gene array; molecular biology: DNA; molecular biology: single polynucleotide polymorphism