Genomewide association study on monoclonal gammopathy of unknown significance (MGUS).

Authors:
Hauke Thomsen, Dr.
Hauke Thomsen, Dr.
GeneWerk GmbH
Senior Bioinformatician
Bioinformatics, Biostatistics, Genetics
Heidelberg, Baden-Württemberg/Germany | Germany
Chiara Campo
Chiara Campo
German Cancer Research Center (DKFZ)
Niels Weinhold
Niels Weinhold
Institute of Cancer Research
United Kingdom
Ludek Pour
Ludek Pour
University Hospital Brno
Evzen Gregora
Evzen Gregora
University Hospital Kralovske Vinohrady
Pavel Vodicka
Pavel Vodicka
Institute of Experimental Medicine
Czech Republic
Ludmila Vodickova
Ludmila Vodickova
Institute of Experimental Medicine
Czech Republic

Eur J Haematol 2017 Jul 24;99(1):70-79. Epub 2017 May 24.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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 . 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 ), 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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http://dx.doi.org/10.1111/ejh.12892DOI Listing

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July 2017
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