Deciphering the genetics and mechanisms of predisposition to multiple myeloma.
Multiple Myeloma
/ genetics
Humans
Genetic Predisposition to Disease
Genome-Wide Association Study
B-Cell Maturation Antigen
/ genetics
Polymorphism, Single Nucleotide
Mendelian Randomization Analysis
B-Lymphocytes
/ immunology
Case-Control Studies
Transmembrane Activator and CAML Interactor Protein
/ genetics
Male
Telomere
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
received:
03
01
2024
accepted:
24
07
2024
medline:
6
8
2024
pubmed:
6
8
2024
entrez:
5
8
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39103364
doi: 10.1038/s41467-024-50932-7
pii: 10.1038/s41467-024-50932-7
doi:
Substances chimiques
B-Cell Maturation Antigen
0
TNFRSF13B protein, human
0
Transmembrane Activator and CAML Interactor Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6644Subventions
Organisme : Vetenskapsrådet (Swedish Research Council)
ID : 2017-02023
Organisme : Vetenskapsrådet (Swedish Research Council)
ID : 2018-00424
Informations de copyright
© 2024. The Author(s).
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