Inherited genetic susceptibility to monoclonal gammopathy of unknown significance

Neils Weinhold, David C. Johnson, Andrew C. Rawstron, Asta Försti, Chi Doughty, Jayaram Vijayakrishnan, Peter Broderick, Nasrin B. Dahir, Dil B. Begum, Fay J. Hosking, Kwee Yong, Brian A. Walker, Per Hoffmann, Thomas W. Mühleisen, Christian Langer, Elisabeth Dörner, Karl-Heinz Jöckel, Lewin Eisele, Markus M. Nöthen, Dirk Hose, Faith E. Davies, Hartmut Goldschmidt, Gareth J. Morgan, Kari Hemminki, Richard S. Houlston

Key points

  • Inherited genetic variation increases risk to developing multiple myeloma through predisposition to MGUS.

  • Loci identified that increase risk of developing MGUS include 2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2 and 22q13.1.


Monoclonal gammopathy of undetermined significance (MGUS), a pre-malignant clone of plasma cells producing a monoclonal paraprotein, is present in ~2% of individuals >50 years. The increased risk of multiple myeloma (MM) in the relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common SNPs at 2p23.3(rs6746082), 3p22.1(rs1052501), 3q26.2(rs10936599), 6p21.33(rs2285803), 7p15.3(rs4487645), 17p11.2(rs4273077) and 22q13.1(rs877529) have recently been shown to influence MM risk. To examine the impact of these 7 SNPs on MGUS we analyzed two case-control series totaling 492 cases and 7,306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P<0.02) for rs1052501, rs2285803, rs4487645, rs4273077. SNP associations were independent with risk increasing with a larger number of risk alleles carried (per allele odds ratio=1.18; P<10-7). Collectively these data are consistent with a polygenic model of disease susceptibility to MGUS and provide support for genetic variation influencing MM risk through predisposition to MGUS.

  • Submitted October 21, 2013.
  • Accepted January 5, 2014.