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Deciphering the genetics and mechanisms of predisposition to multiple myeloma.
- Source :
-
Nature communications [Nat Commun] 2024 Aug 05; Vol. 15 (1), pp. 6644. Date of Electronic Publication: 2024 Aug 05. - Publication Year :
- 2024
-
Abstract
- Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Mendelian Randomization Analysis
B-Lymphocytes immunology
B-Lymphocytes metabolism
Case-Control Studies
Transmembrane Activator and CAML Interactor Protein genetics
Male
Telomere genetics
Multiple Myeloma genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
B-Cell Maturation Antigen genetics
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 39103364
- Full Text :
- https://doi.org/10.1038/s41467-024-50932-7