Risk Of Childhood Acute Lymphoblastic Leukemia Research Articles

Examination of HFE associations with childhood leukemia risk and extension to other iron regulatory genes

Hereditary hemochromatosis (HFE) variants correlating with body iron levels have shown associations with cancer risk, including childhood acute lymphoblastic leukemia (ALL). Using a multi-ethnic sample of cases and controls from Houston, TX, we examined two HFE variants (rs1800562 and rs1799945), one transferrin receptor gene (TFRC) variant (rs3817672) and three additional iron regulatory gene (IRG) variants (SLC11A2 rs422982; TMPRSS6 rs855791 and rs733655) for their associations with childhood ALL. Being positive for either of the HFE variants yielded a modestly elevated odds ratio (OR) for childhood ALL risk in males (1.40, 95% CI=0.83–2.35), which increased to 2.96 (95% CI=1.29–6.80) in the presence of a particular TFRC genotype for rs3817672 (Pinteraction=0.04). The TFRC genotype also showed an ethnicity-specific association, with increased risk observed in non-Hispanic Whites (OR=2.54, 95% CI=1.05–6.12; Pinteraction with ethnicity=0.02). The three additional IRG SNPs all showed individual risk associations with childhood ALL in males (OR=1.52–2.60). A polygenic model based on the number of variant alleles in five IRG SNPs revealed a linear increase in risk among males with the increasing number of variants possessed (OR=2.0 per incremental change, 95% CI=1.29–3.12; P=0.002). Our results replicated previous HFE risk associations with childhood ALL in a US population and demonstrated novel associations for IRG SNPs, thereby strengthening the hypothesis that iron excess mediated by genetic variants contributes to childhood ALL risk.

Polycyclic aromatic hydrocarbons in residential dust and risk of childhood acute lymphoblastic leukemia

Several polycyclic aromatic hydrocarbons (PAHs) are known or probable human carcinogens. We evaluated the relationship between PAH exposure and risk of childhood acute lymphoblastic leukemia (ALL) using concentrations in residential dust as an exposure indicator. We conducted a population-based case-control study (251 ALL cases, 306 birth-certificate controls) in Northern and Central California from 2001 to 2007. We collected residential dust using a high volume small surface sampler (HVS3) (n=185 cases, 212 controls) or by sampling from participants׳ household vacuum cleaners (n=66 cases, 94 controls). We evaluated log-transformed concentrations of 9 individual PAHs, the summed PAHs, and the summed PAHs weighted by their carcinogenic potency (the toxic equivalence). We calculated odds ratios (ORs) and 95% confidence intervals (CI) using logistic regression adjusting for demographic characteristics and duration between diagnosis/reference date and dust collection. Among participants with HVS3 dust, risk of ALL was not associated with increasing concentration of any PAHs based on OR perln(ng/g). Among participants with vacuum dust, we observed positive associations between ALL risk and increasing concentrations of benzo[a]pyrene (OR perln[ng/g]=1.42, 95% CI=0.95, 2.12), dibenzo[a,h]anthracene (OR=1.98, 95% CI=1.11, 3.55), benzo[k]fluoranthene (OR=1.71, 95% CI=0.91, 3.22), indeno[1,2,3-cd]pyrene (OR=1.81, 95% CI=1.04, 3.16), and the toxic equivalence (OR=2.35, 95% CI=1.18, 4.69). The increased ALL risk among participants with vacuum dust suggests that PAH exposure may increase the risk of childhood ALL; however, reasons for the different results based on HVS3 dust samples deserve further study.

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk

Genome-wide association studies have identified multiple risk loci for childhood acute lymphoblastic leukemia (ALL), but mostly in European/White populations, despite Hispanics having a greater risk. We re-examined single nucleotide polymorphisms (SNPs) of known associations with childhood ALL and known human leukocyte antigen (HLA) region lymphoma risk markers in a multi-ethnic population. Significant associations were found in two ARID5B variants (rs7089424 and rs10821936). We replicated a strong risk association in non-Hispanic White males with rs2395185, a protective marker for lymphoma. Another HLA region marker, rs2647012, showed a risk association among Hispanics only, while a strong protective association was found with rs1048456, a follicular lymphoma risk marker. Our study validated this new case–control sample by confirming genetic markers associated with childhood ALL, and yielded new associations with lymphoma markers. Despite positive results, our study did not provide any clues as to why Hispanics have a higher susceptibility to childhood leukemia, suggesting that environmental factors may have a strong contribution.

MTHFR gene polymorphism in acute lymphoblastic leukemia among North Indian children: a case–control study and meta-analysis updated from 2011

Studies on the association of methylenetetrahydrofolate reductase (MTHFR) genotype in childhood acute lymphoblastic leukemia (ALL) have yielded conflicting results. The present study examines this association in north Indian children with ALL and includes an updated meta-analysis. MTHFR (677 and 1298) genotype of children with ALL and healthy adult controls were done by the PCR-restriction fragment length polymorphism (PCR-RFLP) method and were compared using various models of inheritance. A total of 150 patients and 300 controls were included. The 677T allele was found protective (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.04-0.94), whereas 1298C allele led to an increase in risk (OR 4.44, 95% CI 2.19-8.99) of childhood ALL. Meta-analysis included 31 and 27 studies examining the association of 677 and 1298 genotypes, respectively. The 677 C -> T polymorphism was protective (OR 0.90, 95% CI 0.82-0.99). Protection was more pronounced in folate-sufficient populations as compared with those not covered by folate fortification guidelines. The 1298A->C polymorphism was associated with a marginal increase in risk (OR 1.19, 95% CI 1.01-1.40).

The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia

AbstractKiller cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIR gene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk. Genotyping of 16 KIR genes, along with HLA class I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIR genes, KIR haplotypes, and combinations of KIR-HLA ligands were tested for disease association using logistic regression analyses. KIR A/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIR genotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4 allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIR genes and their HLA ligands in childhood ALL etiology that may vary among ethnic groups.

Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group

Germline variants in IKZF1, ARID5B, and CEBPE as risk factors for adult-onset acute lymphoblastic leukemia: an analysis from the GMALL study group

The EPHX1 rs1051740 Polymorphism Is Associated with Childhood Acute Lymphoblastic Leukemia in a Korean Population

Microsomal epoxide hydrolase (EPHX1) is involved in the activation and detoxification of exogenous chemicals. Genetic polymorphisms in EPHX1 have been associated with the development of leukemia. To investigate an association between single-nucleotide polymorphisms (SNPs) of EPHX1 and risk factors for childhood acute lymphoblastic leukemia (ALL) in Korean children, we genotyped two SNPs, Tyr113His (rs1051740) and His139Arg (rs2234922) in 185 childhood ALL cases and 536 healthy controls. Genotyping for these two SNPs was performed by simplex pyrosequencing assay and high-resolution melt analysis, respectively. We found that the Tyr113His genotype was associated with a decreased risk of childhood ALL (odds ratio, OR = 0.64, 95% confidence interval, CI = 0.43 - 0.93; p = 0.02). There was no association between His139Arg and the combined genotypes and the risk of childhood ALL. These results suggest that the EPHX1 113TyrHis genotype may protect against leukemogenesis in childhood.

Association of the 3′UTR FOXO3a Polymorphism rs4946936 with an Increased Risk of Childhood Acute Lymphoblastic Leukemia in a Chinese Population

Background/Aims: FOXO3a is an essential tumor suppressor that regulates the mechanisms of tumorigenesis and leukemogenesis. FOXO3a polymorphisms have not been reported previously associated with an increased risk for childhood acute lymphoblastic leukemia (ALL). In this study, the rs4946936 polymorphism located in the 3'UTR of FOXO3a was selected to evaluate its relationship with a risk for ALL in Chinese children. Methods: Questionnaires, SNaPshot genotyping, real-time PCR, cell transfection and dual luciferase reporter assays were used in this study. Results: Parental alcohol consumption and whether the child's house had been painted had significantly different distributions among the cases and controls. In addition, the C to T mutation was significantly associated with the risk for ALL. We determined that FOXO3a expression levels in patients with the CT or TT genotype were significantly higher than those of patients with the CC genotype. The T allele significantly increased the expression levels in luciferase assays and affected the binding affinity of miR-223 to the FOXO3a 3'UTR. Conclusion: Rs4946936 in FOXO3a was highly associated with an increased risk of childhood ALL in a Chinese population.

Using a Bayesian Hierarchical Model for Identifying Single Nucleotide Polymorphisms Associated with Childhood Acute Lymphoblastic Leukemia Risk in Case-Parent Triads

Childhood acute lymphoblastic leukemia (ALL) is a condition that arises from complex etiologies. The absence of consistent environmental risk factors and the presence of modest familial associations suggest ALL is a complex trait with an underlying genetic component. The identification of genetic factors associated with disease is complicated by complex genetic covariance structures and multiple testing issues. Both issues can be resolved with appropriate Bayesian variable selection methods. The present study was undertaken to extend our hierarchical Bayesian model for case-parent triads to incorporate single nucleotide polymorphisms (SNPs) and incorporate the biological grouping of SNPs within genes. Based on previous evidence that genetic variation in the folate metabolic pathway influences ALL risk, we evaluated 128 tagging SNPs in 16 folate metabolic genes among 118 ALL case-parent triads recruited from the Texas Children’s Cancer Center (Houston, TX) between 2003 and 2010. We used stochastic search gene suggestion (SSGS) in hierarchical Bayesian models to evaluate the association between folate metabolic SNPs and ALL. Using Bayes factors among these variants in childhood ALL case-parent triads, two SNPs were identified with a Bayes factor greater than 1. There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1 rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL. Our findings are suggestive of the role of inherited genetic variation in the folate metabolic pathway on childhood ALL risk, and they also suggest the utility of Bayesian variable selection methods in the context of case-parent triads for evaluating the role of SNPs on disease risk.

Hsa-miR-196a2 polymorphism increases the risk of acute lymphoblastic leukemia in Chinese children

Acute lymphoblastic leukemia (ALL) is a major cause of mortality and morbidity in childhood, and the causes of ALL are not completely understood. microRNAs (miRNAs) regulate various biological processes including organ development, cell growth regulation, cell differentiation, apoptosis, and tumorigenesis. We performed a case–control study with 570 childhood ALL cases and 673 cancer-free controls to investigate the association between hsa-miR-196a2 rs11614913 T>C polymorphism and ALL risk. The bioinformatics was used to estimate the potential target of hsa-miR-196a2. In the present study, the hsa-miR-196a2 variant TC heterozygote, and CC/TC genotypes were found to be associated with a significantly increased childhood ALL risk, compared with the TT wild-type homozygote (adjusted OR=1.50, 95% CI=1.15–1.95 for TC and OR=1.40, 95% CI=1.09–1.79 for CC/TC). Further, the difference was pronounced in younger (≤6) subjects or parental non-drinker. The significance of the increased risk is more obvious than the higher treatment branch. Additionally, we found that the rs11614913 TC genotype can increase B-phenotype ALL risk (OR=1.37, 95% CI=1.07–1.76). Finally, combination of three bioinformatics approaches revealed that HOXC8 may be the target gene of hsa-miR-196a2. Taken together, our finding suggested that hsa-miR-196a2 rs11614913 T>C may increase the risk of childhood ALL. Large studies with the function of hsa-miR-196a2 are needed in the further study.

High Resolution Melting Analyses For Genetic Variants in ARID5B and IKZF1 with Childhood Acute Lymphoblastic Leukemia Susceptibility Loci In Taiwan

Introduction Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease including multiple subtypes, defined on the basis of cell lineage and chromosome anomalies. Previous genome-wide association (GWA) studies report that several ARID5B and IKZF1 single nucleotide polymorphisms (SNPs) are associated with the incidence of ALL. However, high resolution melting analysis (HRM) supplies a faster and more convenient technique to detect SNPs. We applied HRM to detect the SNPs in ARID5B and IKZF1 gene. Method Seventy-nine pediatric ALL patients and 80 healthy controls were enrolled. Polymorphic variants of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) were detected by HRM method. The SNPs were further analyzed the association with childhood ALL. Result We evaluated 6 mutations by PCR amplicons (81 -176 bp) using the 96-well Light Cycler system. The primer detail was listed in Table 1. The melting curve data showed the difference in normalized temperature and we easily and accurately extended application of HRM analysis to genotyping of IKZF1 (Figure 1) and ARID5B (Figure 2) gene variants. The genotype distribution and the allele frequencies of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) gene polymorphisms among cases and controls and their association with the risk of childhood ALL were shown in Table 2. The distribution of genotype rs7073837 in ARID5B was significantly different between the ALL group and the control group (P = 0.046), while the distributions for IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs10740055, and rs7089424) were not significantly different. In addition, we analyzed the association for those SNPs with B lineage ALL and found rs7073837 in ARID5B conferred a higher risk for B lineage ALL (odds ratio, OR = 1.70, 95% confidence interval, CI = 1.01-2.87, P = 0.049). Conclusion HRM was a practical method to detect SNPs in ARID5B and IKZF1 gene. We determined the rs7073837 in ARID5B was associated with the risk of childhood B lineage ALL. Disclosures: No relevant conflicts of interest to declare.

Fas Gene Variants in Childhood Acute Lymphoblastic Leukemia and Association with Prognosis

Fas molecule is one of the main important molecules involved in apoptotic cell death. Single nucleotide polymorphisms in the promoter of Fas gene at positions -1377G/A and -670 A/G may affect its expression and play an important role in the pathology of leukemia. In the present study the association between these polymorphisms and risk of the development of acute lymphoblastic leukemia (ALL) in children with ALL compared to cancer-free control subjects was examined by polymerase chain reaction- based restriction fragment length polymorphism. The relationship between the polymorphisms and clinical and laboratory features of the patients and response to therapy were determined. No significant differences in genotype and allele frequencies between the patients and the control subjects at positions -670 and -1377 were detected. Evaluation of the prognostic factors revealed an association between the GG genotype at position -670 and liver involvement in ALL patients (p < 0.04). Although patients with -1377 AA genotype showed shorter mean complete remission duration, the result of survival analysis did not reach to be significant. In conclusion, results of this study showed no contribution of Fas genotypes at positions -670 and -1377 to risk of ALL in children. The association of Fas GG genotype at position -670 with liver involvement in the patients may show its important role in prognosis of ALL.

Gene-Environment Interactions and the Risk of Childhood Acute Lymphoblastic Leukemia: Exploring the Role of Maternal Folate Genes and Folic Acid Fortification

Few studies have evaluated the interaction of folic acid fortification and folate metabolic genes on the risk of childhood acute lymphoblastic leukemia (ALL). Because folate status is influenced by both intake and genetic variation, the objective of this study was to explore maternal folate metabolic gene-folic acid fortification interactions and the risk of childhood ALL. The study population consisted of 120 ALL case-parent triads recruited from Texas Children's Cancer Center between 2003 and 2010. For this analysis, we focused on 13 maternal single nucleotide polymorphisms (SNPs) in 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). Prefortification was defined as delivery before January 1997 and postfortification as delivery in or after January 1997. We used a two-step approach to evaluate gene-environment interactions. First, a case-only approach was used, as this design provides greater power in the assessment of gene-environment interactions compared to other approaches. Second, we confirmed all statistically significant interactions using a log-linear approach among case-parent triads. Only one of 13 interactions evaluated was confirmed in step 2. Specifically, mothers with the minor allele of MTR rs1804742 and who delivered during the prefortification period were at a greater risk of having a child with ALL (OR = 1.54, 95% CI: 0.82–2.88), compared to those mothers who delivered during the postfortification period (OR = 0.81, 95% CI: 0.22–2.99, P for interaction = .03). In one of the few studies to evaluate maternal folate metabolic genotype-folic acid interactions, we found limited evidence that the maternal MTR rs1804742 appeared to interact with higher folic acid levels to influence childhood ALL risk.

Association between MTR A2756G polymorphism and childhood acute lymphoblastic leukemia: a meta-analysis

To date, many studies on the association between methionine synthase (MTR) A2756G and childhood acute lymphoblastic leukemia (ALL) have provided either controversial or inconclusive results. To clarify the effect of MTR A2756G on the risk of childhood acute lymphoblastic leukemia, a meta-analysis of all relevant studies was performed. The fixed effects model showed that the 2756A allele was associated with a decreased risk of childhood ALL compared with the G allele (ORA vs. G = 0.872; 95% CI 0.782–0.974; p = 0.015, I2 = 46.9%). Additionally, when comparing subjects with ALL and controls with AA vs. AG or AA vs. AG + GG (dominant model), significant differences were found in the fixed effects model (ORAA vs. AG = 0.869; 95% CI 0.760–0.994; p = 0.040, I2 = 26.4%; ORAA vs. AG+ GG = 0.858; 95% CI 0.754–0.976; p = 0.020, I2 = 39.6%). In a subgroup analysis in a population with the same background, individuals with the AA genotype had a reduced risk of developing ALL compared to individuals with the AG genotype. In conclusion, our study provides evidence suggesting that MTR A2756G is associated with a reduced risk of developing childhood ALL.

DNA repair gene XRCC1 polymorphisms and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis.

To estimate the relationship between genetic polymorphisms of X-ray repair cross-complementing group 1 (XRCC1) and the susceptibility to childhood acute lymphoblastic leukemia (ALL). Relevant case-control studies were enrolled in the meta-analysis. We applied Rev Man 4.2 software to pool raw data and test studies' heterogeneity and to calculate the incorporated odds ratio (OR) and 95% confidence interval (95% CI). Our data showed that the OR for the Gln allele of the Arg399Gln polymorphism, compared with the Arg allele, was 1.35 (95% CI, 1.16-1.57; P<0.0001) for childhood ALL patients. Similarly, the homozygous genotype Gln/Gln and heterozygous genotype Arg/Gln both significantly increased the risk of childhood ALL compared with the wild genotype Arg/Arg (OR =1.58; 95% CI, 1.13-2.21; P=0.008; OR =1.51; 95% CI, 1.21-1.87; P=0.0002). The dominant model of Arg399Gln was associated with childhood ALL risk (OR =1.54; 95% CI, 1.25-1.89; P<0.0001). The ethnic subgroup analysis demonstrated that the Gln allele in all five ethnic groups was prone to be a risk factor for childhood ALL just with different degrees of correlation while Arg194Trp SNP showed a protective or risk factor or irrelevant thing in different races. XRCC1 399 polymorphism may increase the risk of childhood ALL. Different ethnic groups with some gene polymorphism have different disease risks.

Fetal growth and childhood acute lymphoblastic leukemia: Findings from the childhood leukemia international consortium

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth-weight-for-gestational-age and proportion of optimal birth weight (POBW)-were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. © 2013 UICC.

Polymorphism of CYP1A1 gene and susceptibility to childhood acute lymphoblastic leukemia in Egypt

The origin of acute lymphoblastic leukemia (ALL) may be explained by a combination of genetic susceptibility and environmental exposure. We aimed to study the frequency of CYP1A1 allelic variants in Egyptian patients with ALL, to evaluate their role in the development of ALL and to correlate these allelic variants with clinical and biological characteristics of the patients. Polymorphism of CYP1A1*2A, *2B and *4 alleles was examined in 186 Egyptian children with ALL and 200 normal individuals using polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP). A higher prevalence of the CYP1A1*4 allele was found in patients with ALL than in the normal population (19.4%vs. 10.0%, odds ratio [OR] = 2.160, 95% confidence interval [CI] = 1.200–3.89, p = 0.01), especially in the homozygous variant (OR = 6.6, 95% CI = 2.23–19.58, p = 0.001) and in male patients (p = 0.005), particularly those aged 2–10 years (OR = 5.214, 95% CI = 1.535–17.706, p = 0.008). CYP1A1*2A showed a significant difference between age groups (p = 0.046), with a higher incidence in the 10–17-year-old group (21.1%). Multivariate analysis showed that only the CYP1A1*4 allele remained as a probable independent risk factor for ALL development (OR = 2.250, 95% CI = 1.244–4.069; p = 0.007). Our results suggest that polymorphic variants in the CYP1A1*4 gene may increase the risk of childhood ALL, particularly in male patients aged 2–10 years.

Association of three polymorphisms in ARID5B, IKZF1and CEBPE with the risk of childhood acute lymphoblastic leukemia in a Chinese population

Recent genome-wide association studies (GWAS) that focus on childhood acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15years old, have found evidence that single nucleotide polymorphisms (SNPs) in IKZF1 (7p12.2), ARID5B (10q21.2) and CEBPE (14q11.2) are strongly related to the risk of childhood ALL. These polymorphisms may lead to abnormal expression and dysfunction of the corresponding transcription factors and are likely to increase the risk of ALL. To validate the relationship between these SNPs and the risk of childhood ALL in Chinese population, we conducted a case–control study of 570 ALL cases and 673 controls. We determined that the SNP rs10821936 in ARID5B was statistically significantly associated with the risk of childhood ALL (P<0.0001). The results were also significant for the subgroup analysis of high-risk, medium-risk and low-risk ALL as well as B-lineage ALL. Statistically significant differences were not found in the SNPs for IKZF1 and CEBPE. In conclusion, ARID5B rs10821936 could serve as a potential biomarker for assessing the risk of childhood ALL in Chinese children.

Maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood acute lymphoblastic leukemia

Discovering genetic predictors of childhood acute lymphoblastic leukemia (ALL) necessitates the evaluation of novel factors including maternal genetic effects, which are a proxy for the intrauterine environment, and robust epidemiologic study designs. Therefore, we evaluated five maternal and offspring xenobiotic metabolism haplotypes and the risk of childhood ALL among 120 case-parent triads. Two of the five haplotypes were significantly associated with risk: GSTM3/GSTM4 (P=0.01) and GSTP1 (P=0.02). The EPHX1 haplotype was marginally associated with risk (P=0.05), whereas haplotypes in CYP1B1 and GSTA4 were not. Our results suggest genetic variation in xenobiotic metabolism is important in childhood ALL etiology.

Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia.

We examine the association between exposure to herbicides and childhood acute lymphoblastic leukemia (ALL). Dust samples were collected from homes of 269 ALL cases and 333 healthy controls (<8 years of age at diagnosis/reference date and residing in same home since diagnosis/reference date) in California, using a high-volume surface sampler or household vacuum bags. Amounts of agricultural or professional herbicides (alachlor, metolachlor, bromoxynil, bromoxynil octanoate, pebulate, butylate, prometryn, simazine, ethalfluralin, and pendimethalin) and residential herbicides (cyanazine, trifluralin, 2-methyl-4-chlorophenoxyacetic acid (MCPA), mecoprop, 2,4-dichlorophenoxyacetic acid (2,4-D), chlorthal, and dicamba) were measured. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Models included the herbicide of interest, age, sex, race/ethnicity, household income, year and season of dust sampling, neighborhood type, and residence type. The risk of childhood ALL was associated with dust levels of chlorthal; compared to homes with no detections, ORs for the first, second, and third tertiles were 1.49 (95% CI: 0.82-2.72), 1.49 (95% CI: 0.83-2.67), and 1.57 (95% CI: 0.90-2.73), respectively (P-value for linear trend=0.05). The magnitude of this association appeared to be higher in the presence of alachlor. No other herbicides were identified as risk factors of childhood ALL. The data suggest that home dust levels of chlorthal, and possibly alachlor, are associated with increased risks of childhood ALL.