RESUMO
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.
Assuntos
Antígeno de Maturação de Linfócitos B , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mieloma Múltiplo , Polimorfismo de Nucleotídeo Único , Mieloma Múltiplo/genética , Humanos , Antígeno de Maturação de Linfócitos B/genética , Análise da Randomização Mendeliana , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Masculino , Telômero/genéticaAssuntos
Conservadores da Densidade Óssea , Doenças Ósseas , Neoplasias Ósseas , Mieloma Múltiplo , Humanos , Ácido Zoledrônico/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Difosfonatos/uso terapêutico , Doenças Ósseas/tratamento farmacológico , Doenças Ósseas/etiologia , Doenças Ósseas/prevenção & controle , Osso e Ossos , Conservadores da Densidade Óssea/uso terapêuticoRESUMO
Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.