Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15. [Display omitted] •SNP rs6877329 underlies the association between 5q15 and multiple myeloma (MM)•SNP rs6877329 forms a chromatin-looping interaction with the ELL2 promoter•rs6877329-C risk allele reduces enhancer activity in MM•rs6877329-C confers lower ELL2 expression in MM patients Li et al. find that rs6877329 underlies the 5q15 MM risk locus. Functional data demonstrate that rs6877329 resides within an enhancer that physically interacts with the ELL2 promoter. The rs6877329-C risk allele reduces enhancer activity and is associated with reduced ELL2 expression in MM patients.