Predictive Modeling of Tacrolimus Dose Requirement Based on High-Throughput Genetic Screening.
Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C0) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C0per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort.
Hypercube Institute, Paris, France.
C
C
Damon
Hypercube Institute, Paris, France.|Paris Descartes University, Paris, France.
M
M
Luck
Department of Clinical Chemistry, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
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L
Toullec
Department of Nephrology, Rouen University Hospital, Rouen, France.
I
I
Etienne
Department of Nephrology, Tours University Hospital, Tours, France.
M
M
Buchler
Department of Nephrology, Caen University Hospital, Caen, France.
B
B
Hurault de Ligny
Department of Nephrology, Amiens University Hospital, Amiens, France.
G
G
Choukroun
Department of Nephrology, Poitiers University Hospital, Poitiers, France.
A
A
Thierry
Department of Nephrology, Rennes University Hospital, Rennes, France.
C
C
Vigneau
Department of Nephrology, Strasbourg University Hospital, Strasbourg, France.
B
B
Moulin
Department of Nephrology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France.
A-E
AE
Heng
Department of Nephrology, Angers University Hospital, Angers, France.
J-F
JF
Subra
Department of Nephrology, Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
C
C
Legendre
Hypercube Institute, Paris, France.
A
A
Monnot
Hypercube Institute, Paris, France.
A
A
Yartseva
Hypercube Institute, Paris, France.
M
M
Bateson
Paris Descartes University, Paris, France.|Department of Clinical Chemistry, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Paris, France.
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P
Laurent-Puig
Department of Nephrology, Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
D
D
Anglicheau
Paris Descartes University, Paris, France.|Department of Clinical Chemistry, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Paris, France.
P
P
Beaune
Paris Descartes University, Paris, France.|Department of Clinical Chemistry, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Paris, France.
M A
MA
Loriot
Paris Descartes University, Paris, France.|Department of Nephrology, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
E
E
Thervet
Paris Descartes University, Paris, France.|Department of Clinical Chemistry, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.|Institut National pour la Santé et la Recherche Médicale (INSERM) U1147, Paris, France.|Department of Nephrology, Georges Pompidou European Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
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Pallet
D015331:Cohort Studies; D005819:Genetic Markers; D005820:Genetic Testing; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D016030:Kidney Transplantation / Q000009:adverse effects*; D015233:Models, Statistical; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage*; D066027:Transplant Recipients
D005819:Genetic Markers; D007166:Immunosuppressive Agents; D016559:Tacrolimus
clinical research/practice; genetics; genomics; immunosuppression/immune modulation; immunosuppressive regimens; pharmacology; translational research/science