Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia.
OBJECTIVE
One of the adverse effects of therapy for acute lymphoblastic leukemia (ALL) is osteonecrosis of the hip. Putative risk factors for osteonecrosis have included being female, white race, and older age. Our goal was to define possible genetic risk factors for osteonecrosis among children treated for newly diagnosed ALL.


METHODS
Using a candidate gene approach, we determined the genotypes for 16 common polymorphisms in genes likely to affect the pharmacokinetics or pharmacodynamics of antileukemic medications in 64 children with ALL. Therapy included glucocorticoids and antifolates. Magnetic resonance imaging of both hips was used to diagnose osteonecrosis, and was performed at similar times from the start of ALL therapy (P =.61) in the 25 patients with and the 39 patients without osteonecrosis (median, 447 days and 443 days, respectively).


RESULTS
In addition to age older than 10 years (odds ratio [OR], 24.2; P =.0001) and white race (OR, 11.1; P =.037), host factors for osteonecrosis included the vitamin D receptor FokI start site CC genotype (OR, 4.5; P =.045), and the thymidylate synthase low activity 2/2 enhancer repeat genotype (OR, 7.4; P =.049).


CONCLUSIONS
Because folate-related and vitamin D-receptor genetic variants have been associated with bone and vasculature morbidity, these pharmacogenetic associations likely reflect the interaction of antileukemic medications with germline sensitivity to drug actions, and might identify ALL patients at highest risk to develop osteonecrosis.
Relling
Mary V
MV
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794, USA. mary.relling@stjude.org
Yang
Wenjian
W
Das
Soma
S
Cook
Edwin H
EH
Rosner
Gary L
GL
Neel
Michael
M
Howard
Scott
S
Ribeiro
Raul
R
Sandlund
John T
JT
Pui
Ching-Hon
CH
Kaste
Sue C
SC
D000367:Age Factors; D002648:Child; D005260:Female; D006615:Hip; D006801:Humans; D007592:Joint Diseases / Q000209:etiology / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D010020:Osteonecrosis / Q000209:etiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000235:genetics*; D012307:Risk Factors; D044465:White People
D018167:Receptors, Calcitriol