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Deciphering the genetics and mechanisms of predisposition to multiple myeloma

M. Went, L. Duran-Lozano, GH. Halldorsson, A. Gunnell, N. Ugidos-Damboriena, P. Law, L. Ekdahl, A. Sud, G. Thorleifsson, M. Thodberg, T. Olafsdottir, A. Lamarca-Arrizabalaga, C. Cafaro, A. Niroula, R. Ajore, A. Lopez de Lapuente Portilla, Z. Ali,...

. 2024 ; 15 (1) : 6644. [pub] 20240805

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019398

Grantová podpora
2017-02023 Vetenskapsrådet (Swedish Research Council)
2018-00424 Vetenskapsrådet (Swedish Research Council)

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.

Broad Institute 415 Main Street Cambridge MA 02142 USA

Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology Box 8905 N 7491 Trondheim Norway

Department of Haematology University Hospital of Copenhagen at Rigshospitalet Blegdamsvej 9 DK 2100 Copenhagen Denmark

Department of Hematology Erasmus MC Cancer Institute 3075 EA Rotterdam The Netherlands

Department of Integrative Medical Biology Umeå University SE 901 87 Umeå Sweden

Department of Internal Medicine 5 University of Heidelberg 69120 Heidelberg Germany

Department of Laboratory Medicine Lund University SE 221 84 Lund Sweden

Department of Radiation Sciences Umeå University SE 901 87 Umeå Sweden

Division of Genetics and Epidemiology The Institute of Cancer Research London SW7 3RP UK

eCODE Genetics Amgen Sturlugata 8 IS 101 Reykjavik Iceland

Faculty of Medicine in Pilsen Charles University 30605 Pilsen Czech Republic

Faculty of Medicine University of Iceland IS 101 Reykjavik Iceland

German Cancer Research Center D 69120 Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

Institute of Experimental Medicine Academy of Sciences of the Czech Republic Prague Czech Republic

Landspitali National University Hospital of Iceland IS 101 Reykjavik Iceland

Lund Stem Cell Center Lund University SE 221 84 Lund Sweden

MSB Medical School Berlin Berlin Germany

Myeloma Center University of Arkansas for Medical Sciences Little Rock AR USA

Perlmutter Cancer Center Langone Health New York University New York NY USA

Section of Hematology Sahlgrenska University Hospital Gothenburg SE 413 45 Sweden

Skåne University Hospital SE 221 85 Lund Sweden

Southern Älvsborg Hospital SE 501 82 Borås Sweden

University Hospital Ostrava and University of Ostrava Ostrava Czech Republic

Citace poskytuje Crossref.org

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