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DOI 10.1038/s41467-024-50932-7

Медицинская библиотека · Nature communications · 2024

Deciphering the genetics and mechanisms of predisposition to multiple myeloma.

Went Molly, Duran-Lozano Laura, Halldorsson Gisli H, Gunnell Andrea, Ugidos-Damboriena Nerea, Law Philip, Ekdahl Ludvig, Sud Amit, Thorleifsson Gudmar, Thodberg Malte, Olafsdottir Thorunn, Lamarca-Arrizabalaga Antton, Cafaro Caterina, Niroula Abhishek, Ajore Ram, Lopez de Lapuente Portilla Aitzkoa, Ali Zain, Pertesi Maroulio, Goldschmidt Hartmut, Stefansdottir Lilja, Kristinsson Sigurdur Y, Stacey Simon N, Love Thorvardur J, Rognvaldsson Saemundur, Hajek Roman, Vodicka Pavel, Pettersson-Kymmer Ulrika, Späth Florentin, Schinke Carolina, Van Rhee Frits, Sulem Patrick, Ferkingstad Egil, Hjorleifsson Eldjarn Grimur, Mellqvist Ulf-Henrik, Jonsdottir Ingileif, Morgan Gareth, Sonneveld Pieter, Waage Anders, Weinhold Niels, Thomsen Hauke, Försti Asta, Hansson Markus, Juul-Vangsted Annette, Thorsteinsdottir Unnur, Hemminki Kari, Kaiser Martin, Rafnar Thorunn, Stefansson Kari, Houlston Richard, Nilsson Björn

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Аннотация

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.

Для цитирования: Went Molly, Duran-Lozano Laura, Halldorsson Gisli H, Gunnell Andrea, Ugidos-Damboriena Nerea, Law Philip, Ekdahl Ludvig, Sud Amit, Thorleifsson Gudmar, Thodberg Malte, Olafsdottir Thorunn, Lamarca-Arrizabalaga Antton, Cafaro Caterina, Niroula Abhishek, Ajore Ram, Lopez de Lapuente Portilla Aitzkoa, Ali Zain, Pertesi Maroulio, Goldschmidt Hartmut, Stefansdottir Lilja, Kristinsson Sigurdur Y, Stacey Simon N, Love Thorvardur J, Rognvaldsson Saemundur, Hajek Roman, Vodicka Pavel, Pettersson-Kymmer Ulrika, Späth Florentin, Schinke Carolina, Van Rhee Frits, Sulem Patrick, Ferkingstad Egil, Hjorleifsson Eldjarn Grimur, Mellqvist Ulf-Henrik, Jonsdottir Ingileif, Morgan Gareth, Sonneveld Pieter, Waage Anders, Weinhold Niels, Thomsen Hauke, Försti Asta, Hansson Markus, Juul-Vangsted Annette, Thorsteinsdottir Unnur, Hemminki Kari, Kaiser Martin, Rafnar Thorunn, Stefansson Kari, Houlston Richard, Nilsson Björn. Deciphering the genetics and mechanisms of predisposition to multiple myeloma.. Nature communications. 2024. DOI: 10.1038/s41467-024-50932-7.

Предметные рубрики MeSH

Multiple MyelomaHumansGenetic Predisposition to DiseaseGenome-Wide Association StudyB-Cell Maturation AntigenPolymorphism, Single NucleotideMendelian Randomization AnalysisB-LymphocytesCase-Control StudiesTransmembrane Activator and CAML Interactor ProteinMaleTelomere
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