Hauke Thomsen1, Chiara Campo1, Niels Weinhold2,3, Miguel Inacio da Silva Filho1, Luděk Pour4, Evžen Gregora5, Pavel Vodicka6,7, Ludmila Vodickova6,7,8, Per Hoffmann9,10, Markus M Nöthen9,11, Karl-Heinz Jöckel12, Christian Langer13, Roman Hajek14, Hartmut Goldschmidt2,15, Kari Hemminki1,16, Asta Försti1,16. 1. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 2. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany. 3. Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA. 4. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic. 5. Department of Hematology, University Hospital Kralovske Vinohrady, Prague, Czech Republic. 6. Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic. 7. Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic. 8. Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic. 9. Institute of Human Genetics, University of Bonn, Bonn, Germany. 10. Department of Biomedicine, University of Basel, Basel, Switzerland. 11. Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn, Germany. 12. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 13. Department of Internal Medicine III, University of Ulm, Ulm, Germany. 14. Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic. 15. National Center of Tumor Diseases, Heidelberg, Germany. 16. Center for Primary Health Care Research, Lund University, Malmö, Sweden.
Abstract
OBJECTIVES: To identify germ line variants contributing to the development of monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant precursor for multiple myeloma (MM). METHODS: We conducted the first genomewide association study (GWAS) on MGUS on 243 German cases with a replication on 294 Czech cases. Identified loci were further analyzed in 1508 German MM patients. New MM loci recently reported in a meta-analysis were also tested in the MGUS GWAS. RESULTS: In GWAS, we identified 10 loci contributing to development of MGUS at P-value threshold of 10-5 . The Czech cohort gave support for two associations (6q26, rs6933936; 7p21.3 rs10251201). In GWAS, rs974120 (8p23.2) reached genomewide significance (P=2.94×10-9 ), with a nominal significance in MM. The locus of rs974120 shows marks of transcriptional activity in leukemia according to ENCODE data. rs10251201 (7p21.3), rs9318227 (13q22.1), and rs10405859 (19q13.32) were associated with markers related to leukemogenesis and immune and inflammatory responses. Two newly identified candidate loci for MM, rs1948915 (8q24.21) and rs8058578 (16p11.2), were nominally associated with MGUS. CONCLUSIONS: These data allow a cautious first proposal for a germ line architecture of MGUS with links to leukemia and autoimmune conditions, the latter agreeing with a family study showing clustering of MGUS with autoimmune diseases.
OBJECTIVES: To identify germ line variants contributing to the development of monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant precursor for multiple myeloma (MM). METHODS: We conducted the first genomewide association study (GWAS) on MGUS on 243 German cases with a replication on 294 Czech cases. Identified loci were further analyzed in 1508 German MM patients. New MM loci recently reported in a meta-analysis were also tested in the MGUS GWAS. RESULTS: In GWAS, we identified 10 loci contributing to development of MGUS at P-value threshold of 10-5 . The Czech cohort gave support for two associations (6q26, rs6933936; 7p21.3 rs10251201). In GWAS, rs974120 (8p23.2) reached genomewide significance (P=2.94×10-9 ), with a nominal significance in MM. The locus of rs974120 shows marks of transcriptional activity in leukemia according to ENCODE data. rs10251201 (7p21.3), rs9318227 (13q22.1), and rs10405859 (19q13.32) were associated with markers related to leukemogenesis and immune and inflammatory responses. Two newly identified candidate loci for MM, rs1948915 (8q24.21) and rs8058578 (16p11.2), were nominally associated with MGUS. CONCLUSIONS: These data allow a cautious first proposal for a germ line architecture of MGUS with links to leukemia and autoimmune conditions, the latter agreeing with a family study showing clustering of MGUS with autoimmune diseases.
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