Dataset Information

Association of genes ARID5B, CEBPE and folate pathway with acute lymphoblastic leukemia in a population from the Brazilian Amazon region.

ABSTRACT: Acute Lymphoblastic Leukemia (ALL) is the most common childhood neoplasia. Studies have shown that susceptibility to ALL may be modulated by genetic variables. Our study investigated 21 genetic variants in the susceptibility of the population of the Brazilian Amazon region to B-cell ALL. The variants of the genes GGH, CEBPE, ARID5B, MTHFR and MTHFD1 were related to a protective effect against the development of ALL, whereas the variant of the gene ATIC was associated with a risk effect. The results suggest that genetic variants analyzed modulate of the risk of developing ALL in the studied population.

SUBMITTER: Carvalho DC

PROVIDER: S-EPMC6906641 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Association of genes <i>ARID5B, CEBPE</i> and folate pathway with acute lymphoblastic leukemia in a population from the Brazilian Amazon region.

Carvalho Darlen Cardoso DC Wanderley Alayde Vieira AV Mello Junior Fernando Augusto Rodrigues FAR Santos André Mauricio Ribeiro Dos AMRD Leitão Luciana Pereira Colares LPC Souza Tatiane Piedade de TP Castro Amanda de Nazaré Cohen Lima de ANCL Magalhães Leandro Lopes de LL Fernandes Marianne Rodrigues MR Carvalho Junior João Augusto Nunes de JAN Khayat André Salim AS Santos Sidney S Assumpção Paulo Pimentel de PP Dos Santos Ney Pereira Carneiro NPC

Leukemia research reports 20191127

Acute Lymphoblastic Leukemia (ALL) is the most common childhood neoplasia. Studies have shown that susceptibility to ALL may be modulated by genetic variables. Our study investigated 21 genetic variants in the susceptibility of the population of the Brazilian Amazon region to B-cell ALL. The variants of the genes GGH, CEBPE, ARID5B, MTHFR and MTHFD1 were related to a protective effect against the development of ALL, whereas the variant of the gene ATIC was associated with a risk effect. The resu ...[more]

PMID: 31867206

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Project description:BackgroundThere is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-cell ALL leukemogenesis remain largely unknown.MethodsWe performed targeted sequencing of ARID5B in germline DNA of 5008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3644 patients from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using dCas9-KRAB-mediated enhancer interference system enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and coimmunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests were 2-sided.ResultsWe identified 54 common variants in ARID5B statistically significantly associated with leukemia risk, all of which were noncoding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P = 5.57 × 10-45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (n = 349 861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P = 8.6 × 10-22 and 2.1 × 10-18, respectively).ConclusionsOur results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.

Dataset Information

Association of genes ARID5B, CEBPE and folate pathway with acute lymphoblastic leukemia in a population from the Brazilian Amazon region.

Publications

Association of genes <i>ARID5B, CEBPE</i> and folate pathway with acute lymphoblastic leukemia in a population from the Brazilian Amazon region.

Similar Datasets

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