RESUMO
Background: The incidence rate of childhood acute lymphoblastic leukemia (ALL) differs worldwide, and the interplay between hemostasis actors and the maladaptive responses to environmental exposures has been explored. It has been proposed that endogenous cortisol, induced by different triggers, would eliminate pre-leukemic clones originated in utero. Herein, we tested if the interaction between CRHR1rs242941 C>A, MC2Rrs1893219 A>G, NR3C1rs41423247 G>C, and GLCCI1rs37972 C>T (players in glucocorticoid secretion) and birth characteristics would be associated with ALL risk. Methods: Children aged <10 years were enrolled within the EMiLI project (period: 2012 to 2020). The study had three steps: (1) observational analysis of birth characteristics (n = 533 cases and 1,603 controls); (2) genotyping to identify single-nucleotide variants (n = 756 cases and 431 controls); and (3) case-only to test gene-environment interactions (n = 402 cases). Genetic syndromes were exclusion criteria. The controls were healthy children. The distribution of the variables was assessed through Pearson's chi-square test. Logistic regression (LR) tests were run fitted and adjusted for selected covariate models to estimate the association risk. Formal interaction analysis was also performed. Genotyping was tested by qPCR with TaqMan probes (NR3C1) or by high-resolution melting (MC2R and GLCCI1). Hardy-Weinberg equilibrium (HWE) was accessed by the chi-square test. The genotype-risk association was tested in co-dominant, dominant, and recessive models. The gene-environment interaction odds ratio (iOR) was assessed in case-only. Results: Low birthweight, C-section, and low maternal schooling were associated with increased risk for ALL, adjOR 2.11, 95% CI, 1.02-4.33; adjOR 1.59, 95% CI, 1.16-2.17; and adjOR 3.78, 95% CI, 2.47-5.83, respectively, in a multiple logistic regression model. MC2R rs1893219 A>G was negatively associated with ALL (AG: OR = 0.68; 95% CI = 0.50-0.94 and GG: OR = 0.60; 95% CI = 0.42-0.85), while for GLCCI1 rs37972 C>T, TT was positively associated with ALL (OR = 1.91; 95% CI = 1.21-3.00). The combination of genotypes for MC2R (AA) and GLCCI1 (TT) increased ALL risk (OR = 2.61; 95% CI = 1.16-5.87). In a multiplicative interaction, MC2R rs1893219 A>G was associated with children whose mothers had less than 9 years of schooling (iOR = 1.99; 95% CI = 1.11-1.55). Conclusion: Our study has demonstrated a significant association between MC2R rs1893219 A>G (reduced risk) and GLCCI1 rs37972 C>T variants (increased risk) and childhood ALL susceptibility. Based on this evidence, genes controlling the HPA axis activity may play a role in leukemogenesis, and further investigation is needed to substantiate our findings.
RESUMO
BACKGROUND: Childhood acute lymphoblastic leukaemia (ALL) is a heterogeneous disease associated with multiple risk factors including genetic susceptibility. Polymorphisms in folate genes have been associated with a protective effect against ALL, although some studies contradict these findings. We aimed to test whether there is an association between the MTHFR rs1801133 variant and the occurrence of B-cell precursor ALL (BCP-ALL) taking in account molecularly distinct subtypes of fetal origin. METHODS: We performed a case-control genotyping study with 2067 samples, 1309 ALL and 758 controls, from children aged ≤ 15 years for MTHFR rs1801133 polymorphism. Risk associations were calculated by odds ratios estimated with unconditional logistic regression, adjusted for frequency-matched ethnic groups. RESULTS: Overall, MTHFR rs1801133 does not impact ALL risk in children with more than 6 years of age. A significant positive association for MTHFR rs1801133 variant was found for ALL with KMT2A-r in the dominant model (adj. OR, 1.48, 95 % CI, 1.01-2.17), while ETV6-RUNX1 and Hyperdiploid subgroups have shown a borderline effect (adj. OR, 1.33, 95 % CI, 0.99-1.78). CONCLUSIONS: The polymorphism MTHFR rs1801133 increased the risk of infant ALL in Brazilian population.
Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologiaRESUMO
A leucemia linfoblástica aguda (LLA) é a neoplasia hematológica mais comum na faixa etária pediátrica, correspondendo a cerca de 75% dos diagnósticos de leucemias. Sua etiologia multifatorial envolve, entre outros fatores, alterações no metabolismo dos folatos. Ingestão de folato via alimentos ou suplementos, bem como a presença de polimorfismos em genes implicados em seu metabolismo vêm sendo estudados como possíveis fatores associados ao risco para a ocorrência de LLA pediátrica. Como o papel destes fatores na etiologia da LLA não está completamente elucidado, este estudo objetivou reunir evidências científicas a respeito da implicação de alterações no metabolismo dos folatos no risco para LLA pediátrica. Foi realizada uma revisão sistemática de estudos observacionais tipo caso-controle, com busca nas bases de dados Medline, Lilacs, Scopus e Web of Science. Foram incluídos na revisão 49 estudos, dos quais, 9 investigaram a relação entre a ingestão de ácido fólico e o risco para LLA pediátrica, e 40 estudaram a suscetibilidade genética à LLA relacionada à presença de polimorfismos nas vias dos folatos. Os resultados demonstram que há evidências limitadas de que a suplementação materna peri-gestacional com ácido fólico possa conferir proteção para a ocorrência de LLA pediátrica...
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in the pediatric age group, accounting for about 75% of leukemia diagnoses. Its multifactorial etiology involves, among other factors, alterations in the folate metabolism. Folic acid intake by food or supplements as well as polymorphisms in folate related genes have been studied as possible factors associated with the risk for pediatric ALL occurrence. The role of these factors in the etiology of ALL is not fully elucidated, and so, this study aimed to gather scientific evidence about the implications of folate metabolism alterations on the risk to pediatric ALL. A systematic review of observational case-control studies was conducted throughout Medline, Lilacs, Scopus and Web of Science databases. Forty-nine studies were included in this review, of which 9 investigated the relationship between folic acid intake and the risk to pediatric ALL, and 40 studied genetic susceptibility to ALL related to the presence of polymorphisms in the folate pathway. The results demonstrated that there is limited evidence that maternal folic acid supplementation before or during pregnancy may provide protection for the occurrence of pediatric ALL. There is no consensus about the role of MTHFR C677T polymorphism in modulating the risk for pediatric ALL, although more studies have shown protection than increased risk for the disease. The results of studies related to MTHFR A1298C, SLC19A1 G80A, TYMS 1494del6 and TYMS 28pb2R / 3R are controversial, suggesting that the effect of those on the risk for ALL can be modified by ethnicity, gender, folate intake, and presence of other genetic variants...