PRKCB is associated with calcineurin inhibitor-induced renal dysfunction in heart transplant recipients.
OBJECTIVE
Single nucleotide polymorphisms (SNPs) in the transforming growth factor-β1 gene (TGFB1) have been inconsistently associated with calcineurin inhibitor (CNI)-induced renal dysfunction following cardiac transplantation. The impact of genetic variants related to the renin-angiotensin-aldosterone system (RAAS) and natriuretic peptides, which are implicated in CNI nephrotoxicity, is unknown. The primary objective of this study was to validate the association between two common variants in TGFB1 (rs1800470, rs1800471) and postcardiac transplant renal function. The secondary objective was to investigate the effect of candidate genes related to the RAAS, natriuretic peptides, and other elements involved in the intracellular signaling of these pathways.


METHODS
We conducted a retrospective cohort study of 158 heart transplant recipients treated with CNIs, and evaluated the association between select SNPs and the estimated glomerular filtration rate as calculated by the Modification of Diet in Renal Disease simplified formula. A total of 273 SNPs distributed in 44 genes were tested.


RESULTS
No association was observed between TGFB1 variants and renal function. One polymorphism in the protein kinase C-β gene (PRKCB; rs11074606), which is implicated in the RAAS intracellular signaling, was significantly associated with post-transplant estimated glomerular filtration rate after adjusting for possible confounders (P=0.00049). This marker is in linkage disequilibrium with two variants located in putative regulatory regions of the gene (rs2283541, rs1013316).


CONCLUSIONS
Our results suggest that PRKCB may be a potential predictor of CNI-induced nephrotoxicity in heart transplant recipients, and could therefore be a promising candidate to identify patients who are most susceptible to this adverse drug reaction.
University of Montreal, Quebec, Canada. kim.lachance@icm-mhi.org
Kim
K
Lachance
Amina
A
Barhdadi
Ian
I
Mongrain
Valérie
V
Normand
Marcin
M
Zakrzewski
Marie-Hélène
MH
Leblanc
Normand
N
Racine
Michel
M
Carrier
Anique
A
Ducharme
Jacques
J
Turgeon
Marie-Pierre
MP
Dubé
Michael S
MS
Phillips
Michel
M
White
Simon
S
de Denus
D000328:Adult; D019703:Calcineurin / Q000008:administration & dosage* / Q000009:adverse effects*; D065095:Calcineurin Inhibitors; D005260:Female; D056726:Genetic Association Studies; D005919:Glomerular Filtration Rate / Q000235:genetics; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D045265:Natriuretic Peptides / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011493:Protein Kinase C / Q000235:genetics*; D064546:Protein Kinase C beta; D051437:Renal Insufficiency / Q000209:etiology* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D065095:Calcineurin Inhibitors; D045265:Natriuretic Peptides; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019703:Calcineurin