Genetic predictors of glucocorticoid-induced hypertension in children with acute lymphoblastic leukemia.
OBJECTIVE
Glucocorticoids are used universally in the remission induction therapy for acute lymphoblastic leukemia (ALL). One of the adverse effects of glucocorticoids is hypertension. Our aim was to define the frequency of and clinical and genetic risk factors for steroid-induced hypertension.


METHODS
We determined the genotypes for 203 candidate polymorphisms in genes previously linked to hypertension or to the pharmacokinetics or pharmacodynamics of antileukemic agents. Hypertension was defined according to the guidelines of the American Academy of Pediatrics; patients were evaluated during the 28-day period of prednisone at 40 mg/m2/day during remission induction of childhood ALL.


RESULTS
Of the 602 children with newly diagnosed ALL who were normotensive pretherapy, 270 (45%) developed hypertension during remission induction. None of the putative risk factors (age, sex, race, white blood cell count, risk group, body mass index, or serum creatinine) was associated with hypertension. Among the polymorphisms genotyped, we identified eight genes (CNTNAP2, LEPR, CRHR1, NTAN1, SLC12A3, ALPL, BGLAP, and APOB) containing variants that were associated with hypertension (chi2 P values 0.002-0.048), several of which interact with the hypothalamus-pituitary-adrenal axis. Polymorphisms in CYP3A4 and CYP3A5 were not associated with hypertension.


CONCLUSIONS
Hypertension is common during ALL remission induction and is related to germline genetic variation.
Kamdem
Landry K
LK
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
Hamilton
Leo
L
Cheng
Cheng
C
Liu
Wei
W
Yang
Wenjian
W
Johnson
Julie A
JA
Pui
Ching-Hon
CH
Relling
Mary V
MV
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005938:Glucocorticoids / Q000009:adverse effects*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000235:genetics*; D007223:Infant; D008297:Male; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D012044:Regression Analysis
D005938:Glucocorticoids; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A