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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Hauke Thomsen
  • Chiara Campo
  • Niels Weinhold
  • Miguel Inacio da Silva Filho
  • Luděk Pour
  • Evžen Gregora
  • Pavel Vodicka
  • Ludmila Vodickova
  • Per Hoffmann
  • Markus M Nöthen
  • Karl-Heinz Jöckel
  • Christian Langer
  • Roman Hajek
  • Hartmut Goldschmidt
  • Kari Hemminki
  • Asta Försti
Organisations
External organisations
  • German Cancer Research Centre
  • University of Arkansas for Medical Sciences
  • Charles University in Prague
  • University of Basel
  • University of Bonn
  • University of Duisburg-Essen
  • University of Ulm
  • University Hospital Brno
  • University Hospital Kralovske Vinohrady
  • University Hospital Ostrava
  • Heidelberg University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • Germ line, Low-risk genes, Myeloma, Susceptibility
Original languageEnglish
Pages (from-to)70-79
Number of pages10
JournalEuropean Journal of Haematology
Volume99
Issue number1
Publication statusPublished - 2017 Jul
Publication categoryResearch
Peer-reviewedYes