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Age-related differences of genetic susceptibility to patients with acute lymphoblastic leukemia.

ABSTRACT: Inherited predispositions to acute lymphoblastic leukemia have been well investigated in pediatric patients, but studies on adults, particularly Chinese patients, are limited. In this study, we conducted a genome-wide association study in 466 all-age Chinese patients with Acute lymphoblastic leukemia (ALL) and 1,466 non-ALL controls to estimate the impact of age on ALL susceptibility in the Chinese population. Among the 17 reported loci, 8 have been validated in pediatric and 1 in adult patients. The strongest association signal was identified at ARID5B locus and gradually decreased with age, while the signal at GATA3 exhibited the opposite trend and significantly impact on adult patients. With genome-wide approaches, germline variants at 2q14.3 rank as the top inherited predisposition to adult patients (e.g., rs73956024, P = 4.3 × 10^-5) and separate the genetic risk of pediatric vs. adult patients (P = 3.6 × 10^-6), whereas variants at 15q25.3 (e.g., rs11638062) have a similar impact on patients in different age groups (overall P = 2.9 × 10^-7). Our analysis highlights the impact of age on genetic susceptibility to ALL in Chinese patients.

SUBMITTER: Hao Q

PROVIDER: S-EPMC8148462 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Age-related differences of genetic susceptibility to patients with acute lymphoblastic leukemia.

Hao Qing Q Cao Minyuan M Zhang Chunlan C Yin Dandan D Wang Yuelan Y Ye Yuanxin Y Zhao Shan S Yang Yunfan Y Chen Ke-Ling KL Ying Binwu B Wang Lanlan L Zhang Yiguan Y Xu Caigang C Zhu Yiping Y Wu Yu Y Gao Ju J Zhao Jun-Ning JN Zhang Yan Y Lu Xiaoxi X

Aging 20210423 9

Inherited predispositions to acute lymphoblastic leukemia have been well investigated in pediatric patients, but studies on adults, particularly Chinese patients, are limited. In this study, we conducted a genome-wide association study in 466 all-age Chinese patients with Acute lymphoblastic leukemia (ALL) and 1,466 non-ALL controls to estimate the impact of age on ALL susceptibility in the Chinese population. Among the 17 reported loci, 8 have been validated in pediatric and 1 in adult patients ...[more]

PMID: 33891562

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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

Age-related differences of genetic susceptibility to patients with acute lymphoblastic leukemia.

Publications

Age-related differences of genetic susceptibility to patients with acute lymphoblastic leukemia.

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