Multiple myeloma (MM) is the most common fatal blood malignancy. It is characterized by an uncontrolled, clonal growth of plasma cells, most often in the bone marrow. Recently, genome-wide association studies have identified DNA sequence variants at 24 independent loci that influence with MM risk. One of the most significant loci is TNFRSF13B at chromosome 17p11.2. This risk allele is represented by 17 DNA sequence variants in high linkage disequilibrium, including 16 non-coding variants and one coding variant resulting in a proline to leucine substitution at amino acid residue 251 (P251L) of unclear significance. Hence, it is conceivable that the TNFRSF13B MM risk allele has coding and/or non-coding effects.
The aim of this proposal is to understand the molecular effects of the TNFRSF13B MM risk allele. For this we will:
1. Investigate if the coding P251L variant within the TNFRSF13B MM risk allele influences TACI signaling.
2. Investigate if the non-coding variants within the TNFRSF13B MM risk allele influence TACI expression and, if so, identify the causal variant(s).
The project will illuminate how one of the strongest MM risk alleles promote development of MM, and thereby provide new insight into MM predisposition.
deCODE - Island
Skåne University Hospital