AbstractBackground This study investigates pharmacogenetic risk factors for bone mineral (apparent) density (BM(A)D) and body composition in pediatric acute lymphoblastic leukemiaDesign and 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 (Δ%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 (Δ lean body mass: non-car-riers:+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.
As the cure rate of pediatric acute lymphoblastic leukemia (ALL) is high,1 research on treatment-related morbidity, like disturbance of body composition and bone mineral density (BMD), is required.2–4 Leukemia and its treatment, especially corticosteroids5 and methotrexate,6 may lead to reduced BMD. However, uniformly treated children show a large variation in disturbance of body composition, BMD reduction and fractures, suggesting a role for pharmacogenetics in the pathogenesis of these problems.4
Several single nucleotide polymorphisms (SNPs) have been shown to influence BMD in adults, especially those of the vitamin-D receptor gene (VDR).7–12 The extent of the influence of VDR SNPs on BMD may be dependent on age and menopausal state.13 In healthy children, only a few studies on the influence of VDR 3′-end SNPs (BsmI, ApaI, TaqI) on BMD have been reported, with conflicting results.14–17 Effects of VDR 5′-promoter SNPs (Cdx-2, GATA) on BMD have not been investigated in healthy children. With regards to body composition (muscle strength and fat mass), it has been demonstrated that the VDR BsmI SNP determines body composition in premenopausal women.18
Another polymorphism frequently reported to be associated with a low BMD for chronological age is the G→T substitution in the Sp1 binding site of the collagen type I alpha 1 gene (COLIA1). This can result in increased expression of collagen type I alpha 1 in the bone matrix.7, 19–21 Studies regarding the relationship between BMD and carrying COLIA1 risk alleles in healthy children show conflicting results.22–25
Haplotypes of the 5′-end of the estrogen receptor alpha gene (ESR1) in which the risk alleles of the PvuI and XbaII SNPs are combined are associated with decreased BMD and fractures in post-menopausal women.26–28 Only a few studies in healthy children have been carried out, showing conflicting results concerning the influence of ESR1 risk alleles on BMD.25, 29 On the other hand, the PvuII and XbaI SNPs are not related to body composition in healthy children.30
In healthy adults, it has been suggested that polymorphisms in the glucocorticoid receptor gene (GR), like BclI and N363S, modulate corticosteroid sensitivity.31,32 This in turn could result in reduced BMD32,33 and disturbed body composition.31,34 Since corticosteroids are considered to cause altered body composition and reduced BMD, we hypothesize that GR SNPs may influence variation in body composition and BMD in pediatric ALL.
To our knowledge, this is the first study investigating the influence of genetic variation of the VDR, COLIA1, ESR1 and GR on BMD, body composition and fracture risk in pediatric ALL patients during and after therapy. The aim of this study is to identify patients at risk for a low BMD for chronological age and a disturbed body composition, in order to develop early preventative interventions.
Design and Methods
In this prospective study, children with newly diagnosed ALL were treated according to the dexamethasone-based protocol of the Dutch Childhood Oncology Group (DCOG-ALL9).35 High-risk criteria were white blood cell count of 50×10/L or over, T-cell immunophenotype, mediastinal mass, central nervous system involvement, testes infiltration, t(9;22) and 11q23/MLL gene rearrangements. The treatment schedules included dexamethasone given in repetitive pulses (cumulative dose: 1,244 mg/m (high-risk) and 1,370 mg/m (non-high risk). Total cumulative dose of methotrexate was 13,650 mg/m in the high-risk protocol and 8,100mg/m in the non-high risk protocol. No patient received central nervous system irradiation.
To determine a potential selection bias, we compared patient characteristics of participants of the current study with those of the total Rotterdam DCOG-ALL9-treated cohort. The Medical Ethical Committee approved the study. Written informed consent according to the Helsinki agreement was obtained from all parents and patients aged 12 years and older.
After reaching complete remission, germ-line genomic DNA was extracted from a minimum of 5.0×10 peripheral blood mononuclear cells using TRIzol reagent (Gibco BRL, Life Technologies) according to the manufacturer’s protocol. The DNA was quantified using spectrophotometry. Figure 1 shows positions of the SNPs which were detected by real-time PCR and hybridization probes (Taqman).
We determined three SNPs at the 3′-end of the VDR gene (BsmI (E8-G+284A, rs1544410), ApaI (E9-T-48G, rs739837), and TaqI (E9-T32C, rs731236).12 Haplotypes were named as previously described.9,12 In our patients, haplotype 1 (baT), haplotype 2 (BAt), haplotype 3 (bAT) and haplotype 4 (BAT) occurred, which combined to eight genotypes encoded 1/1, 1/2, 1/3, 1/4, 2/2, 2/3, 2/4 and 3/3 (3/4 and 4/4 were not observed).
Two other VDR 5′-promoter region SNPs were studied; the G→A substitution in the Cdx-2 binding site (1e-G-1739A, rs11568820) and an A→G substitution in the GATA binding site (1a-A-1012G, rs4516035)[8, 9, 36]. Both 5′-promoter polymorphisms were combined to haplotype 1 (GA), haplotype 2 (GG) and haplotype 3 (AG), combining to six genotypes encoded as 1/1, 1/2, 1/3, 2/2, 2/3 and 3/3.
The Sp1 polymorphism is a G→T substitution affecting a binding site of the Sp1 transcription factor in the first intron of COLIA1 (int1-G+1245T, rs1800012).37 The polymorphism results in three genotypes GG, GT and TT.
We genotyped two polymorphisms in the first intron of ESR1: PvuII (int1-T-397C, rs2234693) and XbaI (int1-A-351G, rs9340799).28 Three haplotype alleles were encoded as haplotype 1 (px), haplotype 2 (PX), and haplotype 3 (pX), combining to six genotypes 1/1, 1/2, 1/3, 2/2, 2/3 and 3/3.
We determined two SNPs of the GR: the BclI (int2-C-646G, rs not available) which combined to the genotypes CC, CG and GG and the N363S (e2-A1218G, rs6195) combining to the genotypes AA, AG and GG.38
Anthropometry data were measured in all patients. Height was measured with a Harpenden stadiometer and weight with standard clinical scales. The body mass index (BMI) was calculated as weight/height2. Height and BMI of the patients were compared with reference values of healthy controls matched for age and sex and expressed as standard deviation scores (SDS).39,40
In patients aged four years and older, dual energy X-ray absorptiometry (DXA, Lunar DPX-L) provided estimates of lean body mass (LBM), percentage fat of the total body (%fatTB), BMD of the total body (BMDTB) and BMD of the lumbar spine (BMDLS). To correct for bone size, we calculated bone mineral apparent density (BMAD) of the lumbar spine with the model BMADLS=BMDLSx(4/(πxwidth)). ‘Width’ is the mean width of the second to the fourth lumbar vertebrae. This model was validated by in vivo volumetric data obtained from magnetic resonance imaging.41 All DXA results were expressed as age-matched and sex-matched SDS.42 Special pediatric software was used for children who weighed less than 30 kg.
Symptomatic fractures, confirmed by radiography, were registered. Fracture incidence rates of the various allelic variants were calculated. In addition, incidence-rate ratios for non-carrier versus carriers were calculated.
Habitual physical activity measured in minutes/week included physical education classes, organized sports, recreational activities, habitual walking/cycling.43 Calcium intake was determined by a detailed food-frequency questionnaire of dairy products.44 Serum calcium, 1,25-dihydroxy-vitamin D and PTH were assessed. Since over time, PTH concentrations were measured on three different immunoanalyzers, concentrations of PTH were expressed as the number of standard deviations above the upper limit of the reference range of the immunoassay used.45
Measurements were performed at diagnosis, after 32 weeks, one year, two years (completion of therapy) and three years (one year after completion of therapy). Differences between non-carriers and carriers in change of end points during the two-year treatment period (Δ1) and during the first year after completion of chemotherapy (Δ2) were investigated. To compare positions of the curves of the different carrier groups, areas under the curves were calculated.
SNPs were tested for deviation from the Hardy Weinberg Equilibrium (HWE) by comparing the observed and expected genotype frequencies using a χ test. We calculated areas under the curves using the trapezium rule. A Mann-Whitney U-test/χ-test was used to compare baseline patient characteristics and areas under the curves for the different carrier groups. Anthropometry, body composition and BMD at diagnosis were compared with normal reference values using a one-sample t-test. Fracture incidence-rate ratios were tested using Poisson statistics. These statistical analyses were performed with SPSS 15.0 (SPSS Inc. Chicago, IL, USA). Differences between the carrier groups in changes of end points (Δ1 and Δ2) were analyzed using repeated measurements analysis (SAS PROC MIXED, SAS Institute Inc., North Carolina, USA), with an unstructured repeated covariance type. We pooled heterozygous and homozygous carriers under a dominant inheritance model. In view of the multiple comparisons, P values of ≤0.01 were considered to be significant. All analyses were carried out according to the intention-to-treat principle; for children who did not complete the study, data prior to elimination were included.
Sixty-nine patients (39 males) were included, with a mean age of 7.4 (range 1.6–16.8) years. Twenty patients were treated with the high-risk protocol and the remaining children received non-high risk treatment. Age, gender and risk-group stratification of the included patients was similar to that of the total DCOG-ALL9-treated cohort, which indicated that the sample constituted a representative selection of the Rotterdam cohort.
The distribution of the genotypes of VDR 3′-end (BsmI/ApaI/TaqI) and 5′-end (Cdx-2/GATA), COLIA1 (Sp1), ESR1 (PvuII/XbaI), and GR (BclI) were in HWE (Table 1). No homozygous carriers and only 3 heterozygous carriers of the GR (N363S) polymorphism were determined (data not shown).
At diagnosis, there was no difference in %fatTB of our sample compared with that of healthy peers. The patients showed a lower BMI and LBM at diagnosis than healthy peers (BMI=−0.51SDS, P<0.01 and LBM=−0.67SDS, P<0.001). There was no difference in baseline BMDTB of our ALL patients compared with healthy peers, whereas BMDLS of the patients was lower than BMDLS of healthy peers (BMDLS=−0.53SDS, P=0.01). However, after correction for bone size, the calculated BMADLS showed no differences between patients and healthy peers (BMADLS=−0.21SDS, P=0.25).
There was no significant difference in baseline anthropometry, body composition and BM(A)D between non-carriers and carriers of any of the SNPs or haplotypes. In addition, there were no significant differences in age, calcium intake and physical activity.
Body composition during/after therapy
During treatment, the whole group of patients showed an increase in BMI (Δ1BMI=+1.43SDS, P<0.001). Consequently, BMI became higher than BMI of healthy peers (area under the curve during treatment: P<0.001). There was no difference in increase of BMI during treatment between non-carriers and carriers of the different allelic variants (Table 2). After completion of treatment, BMI of the patients decreased (Δ2BMI=−0.31SDS, P<0.01), but remained higher than BMI of healthy peers one year after completion of treatment (BMI=+0.60SDS, P<0.001). Furthermore, there was no influence of the carrier status of any of the genotypes on change of BMI after treatment. There were no differences between non-carriers and carriers of the investigated risk alleles in the areas under the curves of BMI either during treatment or during the year after treatment.
During treatment, %fatTB in the patient group was higher than in healthy peers (area under the curve during treatment: P<0.001) and increased significantly (Δ1%fatTB=+1.32SDS, P<0.001). After completion of treatment, %fatTB in the whole study group decreased (Δ2%fatTB=−0.60SDS, P<0.001), but remained higher than in healthy peers (%fatTB=+0.64SDS, P<0.001). A significant difference in gain of %fatTB during treatment was found between non-carriers and carriers of the VDR 5′-end (Cdx-2/GATA) haplotype 3 (non-carriers: Δ1%fatTB=+1.76SDS, carriers Δ1%fatTB=+0.77 SDS; P<0.001) (Table 2). This difference in fat gain between both groups was not evident in the first eight months of treatment, but became obvious during the remaining part of the treatment. No differences in Δ1%fatTB between non-carriers and carriers of any of the other investigated risk alleles were found. Furthermore, Δ2%fatTB of the non-carriers of the investigated SNPs/haplotypes was similar to that of the carriers. There was no difference in the areas under the curve of %fatTB between the various carrier groups during treatment or in the year after treatment.
During treatment, the whole group of patients had a lower LBM than healthy peers (area under the curve during treatment: P<0.001) and it showed no significant change during treatment. In addition, non-carriers showed the same development of LBM during treatment as carriers of the different risk alleles (Table 2). Although LBM of the whole group increased in the year after completion of treatment (Δ2LBM=+0.23SDS, P<0.01), LBM remained lower than in healthy peers (LBM=−0.69SDS, P<0.001). The first year after treatment completed, LBM increased in non-carriers of ESR1 (PvuII/XbaI) haplotype 3, but not in carriers (non-carriers: Δ2LBM=+0.28SDS, carriers: Δ2LBM=−0.55SDS; P<0.01). There was no difference in the Δ2LBM between non-carriers and carriers of the other investigated risk alleles. During treatment and during the year after treatment, there was no difference in the areas under the curves of LBM between the various carrier groups.
BMD during/after therapy
During treatment, BMDLS of the patients remained lower than that of healthy peers (P<0.01). As BMDLS of the whole group did not change either during or after treatment, a year after completion of treatment it was still lower in the patients than in healthy peers (BMDLS=−0.63SDS, P<0.001). BMADLS was only lower in patients than in healthy peers after completion of treatment (P<0.01).
Figure 2 shows the effect of different haplotypes of the VDR 5′-end (Cdx-2/GATA) on BM(A)DLS. Carriers of the VDR 5′-end haplotype 3 had a lower BMDLS and BMADLS than non-carriers (area under the curve BMDLS: P=0.01, area under the curve BMADLS: P=0.03). There was no difference in BM(A)DLS between non-carriers and carriers of haplotype 1 (area under the curve BMDLS: P=0.68, area under the curve BMADLS: P=0.98) or haplotype 2 (area under the curve BMDLS: P=0.91, area under the curve BMADLS: P=0.92) of the VDR 5′-end. No differences in areas under the curves of BM(A)DLS were found between non-carriers and carriers of the other investigated risk alleles. Moreover, no differences were shown for Δ1BM(A)DLS and Δ2BM(A)DLS between non-carriers and carriers of the SNPs/haplotypes (Table 2).
During treatment, BMDTB decreased in patients (Δ1BMDTB=−1.00SDS, P<0.001). One year after diagnosis, the total group of patients developed lower levels of BMDTB than healthy peers (P<0.01). During the year after treatment, BMDTB of the patients increased (Δ2BMDTB=+0.29SDS, P<0.001), but remained lower than that of healthy peers (BMDTB=−0.52SDS, P<0.001). No significant differences in Δ1BMDTB or Δ2BMDTB between non-carriers and carriers of the VDR, COLIA1, ESR1 or GR risk alleles were found (Table 2). In addition, there was no difference in areas under the curves of BMDTB between the various carrier groups either during treatment or during the year after completion of treatment.
Nine patients sustained a fracture during therapy (n=5) or within one year after completion of treatment (n=4). Fractures involved the forearm (n=4), the tibia (n=3), the clavicle (n=1) and a vertebra (n=1). Except for the vertebral compression fracture, all fractures were preceded by minor trauma. The investigated SNPs/haplotypes were not associated with an increased fracture risk (Figure 3).
No differences in serum calcium, PTH and 1,25-dihydroxy-vitamin D were found between non-carriers and carriers of the VDR 5′-end (Cdx-2/GATA) haplotype 3 (Table 3). Moreover, there was no difference in the change of calcium, PTH and 1,25-dihydroxy-vitamin D during therapy and during the year after treatment between non-carriers and carriers of the VDR 5′-end haplotype 3.
Body composition and polymorphisms
None of the genetic variations in the investigated genes (VDR, COLIA1, ESR1 and GR) influenced body composition during pediatric ALL treatment, except for haplotype 3 of the VDR 5′-promoter region (Cdx-2/GATA). Non-carriers of the VDR 5′-end haplotype 3 had a larger gain of body fat during treatment than carriers, suggesting a role for vitamin D in the regulation of body fat during pediatric ALL treatment. The Cdx-2 A-allele increases VDR transcription in the small intestine and may consequently increase calcium absorption.36 Therefore, we hypothesized that non-carriers of the VDR 5′-end haplotype 3 (without the Cdx-2 A-allele) may have relatively lower serum calcium resulting in a relative hyperparathyroidism. This could lead to increased intracellular calcium within adipocytes, inducing lipogenesis.46 However, we found no significant differences in serum calcium or PTH between non-carriers and carriers of the VDR 5′-end haplotype 3. Therefore, it is questionable whether this mechanism indeed plays a role in regulation of body fat during ALL treatment in children.
The current study suggests that carrying ESR1 (PvuII/XbaI) haplotype 3 negatively influences recovery of LBM after completion of treatment, whereas none of the other genes (VDR, COLIA1 and GR) influence body composition after ALL treatment. In adults, polymorphisms in ESR1 have been described to be associated with measures of adiposity,47 although studies on the influence of ESR1 on LBM are not available. In healthy children, the PvuII and XbaI SNPs were not related to body composition.30
BMD and polymorphisms
We found a lower BMDLS in patients carrying the VDR 5′-end (Cdx-2/GATA) haplotype 3 than in non-carriers, which was already present at diagnosis. Despite this lower BMDLS, carriers of the VDR 5′-end haplotype 3 did not show a larger treatment-related loss of BMDLS. Two previous reports showed that presence of the Cdx-2 A-allele protected against the loss of BMD and subsequent osteoporotic fractures in elderly individuals.8,36 This illustrates that aging may influence the effect of genetic variation on BMD.48 Moreover, the present study reports on genotype-based differences in the development of BMD following ALL treatment, while the majority of adult reports examined BMD differences between genotypes without chemotherapy.
We did not find any association between VDR 3′-end (BsmI/ApaI/TaqI) haplotypes and BMD. This is in line with the fact that VDR BsmI and ApaI SNPs did not influence corticosteroid-induced bone loss in adults receiving corticosteroids for rheumatoid arthritis.49 No studies are available on the effects of the VDR 3′-end SNPs on BMD in ALL patients treated with corticosteroids. Studies on the relation between BMD and VDR 3′-end SNPs in healthy children show conflicting results that may be explained by gene-environment interactions, like dietary calcium intake.48,50 In the current study however, calcium intake was adequate with no difference between non-carriers and carriers. Moreover, physical activity could interact with the gene-effect, although there was no difference between non-carriers and carriers. The fact that the individuals in whom the questionnaire was validated had a higher age than our studied ALL patients may have masked a possible gene-physical activity interaction.
We found no influence of polymorphisms of the COLIA1 (Sp1), ESR1 (PvuII/XbaI) and GR (BclI) on BM(A)D. Because the number of included patients was relatively low, validation of the results in larger cohorts is recommended to confirm our results and to exclude the risk of false-negative findings. So far, no studies on the influence of genetic variation of the COLIA1, ESR1 and GR on BM(A)D have been performed in pediatric ALL patients. Several studies in the elderly reported an association between the Sp1 polymorphism and a lower BMD and increased fracture risk.7,21 In pediatric populations this association is less clear. A lower BMD in healthy children carrying the Sp1 T-allele has been reported but this was mainly due to differences in bone size.19,23 The effect of the ESR1 polymorphism on steroid-induced bone loss has not been previously described. Regarding the GR SNPs, the N363S was associated with BMD in healthy adults.32 Our study included no homozygous and 3 heterozygous carriers of the N363S SNP, so no conclusion could be drawn on the effects of this SNP on BMD in pediatric ALL.
The evaluated risk alleles did not influence fracture risk in our cohort of pediatric ALL patients. This lack of association might be explained by other factors contributing to fracture risk, like an increased tendency to fall due to vincristine neuropathy during ALL treatment.
This is the first study investigating the influence of genetic variation of the VDR, COLIA1, ESR1 and GR on body composition, BMD and fracture risk in pediatric ALL. We found the VDR 5′-end (Cdx-2/GATA) haplotype 3 as a protective factor for excessive fat gain during therapy. Moreover, this haplotype 3 of the VDR 5′-promoter was determined as a risk factor for a lower BM(A)DLS at diagnosis, which remained a risk factor for a lower BM(A)DLS over the course of ALL treatment. Carriage of ESR1 (PvuII/XbaI) haplotype 3 negatively influenced recovery of LBM after completion of treatment.
the authors would like to thank Y. de Rijke for her advice on the assessments of biochemical markers and P. Arp and Y. Fang for their technical assistance in SNP genotyping. We would also like to thank A. Darlington for editorial assistance.
- Funding: this work was supported by the Pediatric Oncology Foundation Rotterdam (KOCR).
- Authorship and Disclosures MLW collected data, performed statistical analysis, interpreted data and wrote the manuscript. RDB collected and interpreted data and wrote the manuscript. SMPFM designed research, interpreted data and supervised the manuscript. AGU performed genetic analyses and supervised the manuscript. WCJH supervised the statistical analysis and interpreted data. RP and MMH designed research, interpreted data and supervised the manuscript.
- The authors reported no potential conflicts of interest.
- Received August 28, 2009.
- Revision received October 22, 2009.
- Accepted October 22, 2009.
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