Pharmacogenetic risk factors for altered bone mineral density and body composition in pediatric acute lymphoblastic leukemia.
BACKGROUND
This study investigates pharmacogenetic risk factors for bone mineral (apparent) density (BM(A)D) and body composition in pediatric acute lymphoblastic leukemia


METHODS
We determined the influence of SNPs in 4 genes (vitamin-D receptor (VDR: BsmI/ApaI/TaqI and Cdx-2/GATA), collagen type I alpha 1 (SpI), estrogen receptor 1 (ESR1: PvuII/XbaI), glucocorticoid receptor (BclI)) on body composition, BM(A)D and fracture risk during dexamethasone-based pediatric acute lymphoblastic leukemia treatment. Body composition and BMD were measured repeatedly during and after treatment using dual energy X-ray absorptiometry.


RESULTS
Non-carriers of VDR 5'-end (Cdx-2/GATA) haplotype 3 revealed a significant larger fat gain than carriers (Delta%fat: non-carriers: +1.76SDS, carriers: +0.77SDS, P<0.001). At diagnosis and during therapy, lumbar spine BMD was significantly higher in non-carriers of VDR 5'-end (Cdx-2/GATA) haplotype 3 than in carriers. The other SNPs did not influence BMD or fracture risk during/after treatment. The year after treatment completion, lean body mass increased in non-carriers of ESR1 (PvuII/XbaI) haplotype 3 and decreased in carriers (Delta lean body mass: non-carriers:+0.28SDS, carriers: -0.55SDS, P<0.01).


CONCLUSIONS
Only VDR 5'-end (Cdx-2/GATA) haplotype 3 was identified as protective factor against excessive fat gain and as a risk factor for lower lumbar spine BMD during treatment. Carrying ESR1 (PvuII/XbaI) haplotype 3 negatively influenced recovery of lean body mass after pediatric acute lymphoblastic leukemia treatment.
te Winkel
Mariël L
ML
Department of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, 3015 GJ Rotterdam, the Netherlands.
van Beek
Robert D
RD
de Muinck Keizer-Schrama
Sabine M P F
SM
Uitterlinden
André G
AG
Hop
Wim C J
WC
Pieters
Rob
R
van den Heuvel-Eibrink
Marry M
MM
D000293:Adolescent; D001823:Body Composition / Q000187:drug effects / Q000235:genetics*; D015519:Bone Density / Q000187:drug effects / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D000090602:Collagen Type I, alpha 1 Chain; D003907:Dexamethasone / Q000009:adverse effects; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D011446:Prospective Studies; D018167:Receptors, Calcitriol / Q000235:genetics; D012307:Risk Factors
C000716127:COL1A1 protein, human; D000090602:Collagen Type I, alpha 1 Chain; D047628:Estrogen Receptor alpha; D018167:Receptors, Calcitriol; D003907:Dexamethasone