Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children

Abstract

Background Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on: IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early life infections (presence of older siblings, daycare attendance, and ear infections). Methods Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study (CCLS) were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated for each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early life infections using logistic regression models that included an interaction term. Results Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified; rs7780012, OR=0.50, 95% confidence interval (CI): 0.35-0.71 (p=0.004); rs7089424, OR=2.12, 95% CI: 1.70-2.65 (p=1.16 x 10-9); rs4982731, OR=1.69, 95% CI: 1.37-2.08 (p=2.35 x 10-6), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early life infections with ALL risk was not observed. Conclusions Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Impact Results implicate the ARID5B, CEBPE and IKZF1 genes in the pathogenesis of childhood ALL.

Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor

“…‡Not represented in clinical genomic/SNP databases, but detected in one of >900 patients with myelodysplastic syndrome and reports of two individual patients with chronic thrombocytopenia 29–31§Not represented in clinical genomic/SNP databases, amino acid highly conserved, estimated allele frequency <0.1%.¶Not represented in clinical genomic/SNP databases, amino acid not highly conserved, estimated allele frequency <0.1%.**A high-resolution DNA array from peripheral blood mononuclear cells (in remission, in A.2.2) was performed as described in online supplementary table 1; the ARID5B risk allele was previously described in 21–23.††A high-resolution array from bone marrow cells at timepoint of leukaemia diagnosis pointing at secondary somatic mutations is shown in online supplementary table 1, in brief: 55,XY,+X,del(3)(p25.3p25.2),del(3)(q11.1q11.2),del(3)(q23q24),+4,del(7)(p12.2)/IKZF1,+8,+9,+10,sUPD(10)(q21.2q21.3),del(13)(q12.2),+14,del(14)(q32.12q32.13),dup(17)(q12q25.3),+18,+21,+21.‡‡Patient-reported and/or physician-documented.§§Phagocytosis and oxidative burst (dihydrorhodamine 123 flow cytometric [DHR FACS] analysis).¶¶Light microscopy, May Gruenwald-Giemsa.***ATP release, impact-R, aggregometry.†††Unbiased first interpretation of immune histochemistry.ALL, acute lymphoblastic leukaemia; ITP, immune thrombocytopenia; n.a., not applicable; n.d., not determined.…”

“…**A high-resolution DNA array from peripheral blood mononuclear cells (in remission, in A.2.2) was performed as described in online supplementary table 1; the ARID5B risk allele was previously described in 21–23.…”

“…No evidence has yet been found for a specific second oncogenic hit or programme in patients with a germline ETV6 mutation 10. Analyses of the landscape of genetic alterations in HD-ALL have shown that deletions of ETV6 or AT rich interactive domain 5B ( ARID5B ) and SNPs of the latter are linked with HD-ALL, among many other oncogenic factors, and might be acquired or constitutional 16–23. Moreover, although ARID5B risk alleles for ALL have been confirmed in different studies,21 22 24 lower ARID5B expression in individuals with certain risk alleles was observed23 and downregulation of ARID5B on the grounds of dysfunctional IKAROS has been shown to contribute to high-risk ALL,25 the exact mechanisms of leukaemia susceptibility that are linked to ARID5B alleles remain to be elucidated.…”

Association of ARID5B gene variants with acute lymphoblastic leukemia in Yemeni children

“…Several genome wide and candidate gene association studies have reported strong associations between ARID5B SNPs and ALL risk in different populations. [9][10][11][12]15,[17][18][19][20][27][28][29][30] Previously, GWA studies have been conducted in populations of European, Hispanic, and African American ancestry. Our findings in Yemeni population are in agreement with these studies, confirming ARID5B SNPs as general susceptibility markers for ALL.…”

Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

“…Furthermore, abnormal expression of ARID5B pauses maturation of B-cells in the developing fetus and adds to leukemogenesis [58]. Multiple studies have suggested that IKZF1 and ARID5B SNPs are positively correlated with ALL [59][60][61][62][63][64][65][66][67][68][69][70][71], but studies showing the connection between ARID5B expression and ARID5B SNPs were missing. Ge et al (2018) demonstrated that the deletion of a single copy of IKZF1 correlates with low expression of ARID5B and that ARID5B expression is positively regulated by Ikaros [72].…”