Abstract
SummaryChronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10−13, odds ratio = 1.35), localizes to a super-enhancer defined by extensive histone H3 lysine 27 acetylation in intron 3 of B cell lymphoma 2 (BCL2)-modifying factor (BMF). The rs539846-A risk allele alters a conserved RELA-binding motif, disrupts RELA binding, and is associated with decreased BMF expression in CLL. These findings are consistent with rs539846 influencing CLL susceptibility through differential RELA binding, with direct modulation of BMF expression impacting on anti-apoptotic BCL2, a hallmark of oncogenic dependency in CLL.
Highlights
Genome-wide association studies (GWASs) frequently have identified statistically significant associations within noncoding regions of the genome, the underlying causal variant has been elucidated in only a few instances
Fine-Mapping of the 15q15.1 chronic lymphocytic leukemia (CLL) Risk Locus A previous genome-wide association studies (GWASs) reported an association between rs8024033 at 15q15.1 and CLL risk (Berndt et al, 2013)
To refine the association signal, we performed fine-mapping of the 15q15.1 CLL risk locus by imputation of our European GWAS to 1000 Genomes Project (Abecasis et al, 2012) and UK10K (UK10K Consortium et al, 2015) reference panels
Summary
Genome-wide association studies (GWASs) frequently have identified statistically significant associations within noncoding regions of the genome, the underlying causal variant has been elucidated in only a few instances. GWASs of chronic lymphocytic leukemia (CLL) have identified 31 risk loci, with the signal annotating B cell lymphoma 2 (BCL2)-modifying factor (BMF) at 15q15.1 being highly robust (Berndt et al, 2013, 2016; Crowther-Swanepoel et al, 2010; Di Bernardo et al, 2008; Slager et al, 2011, 2012; Speedy et al, 2014). Elevated expression of the anti-apoptotic protein BCL2 is a hallmark of CLL, driving the accumulation of mature leukemic lymphocytes (Hanada et al, 1993). We sought to identify the causal polymorphism(s) driving the 15q15.1 association with CLL susceptibility as a basis for understanding BCL2 addiction mechanisms in CLL
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