Inherited genetic susceptibility to monoclonal gammopathy of unknown significance.
Monoclonal gammopathy of undetermined significance (MGUS) is present in ∼2% of individuals age >50 years. The increased risk of multiple myeloma (MM) in relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common single-nucleotide polymorphisms (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 7306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P < .02) for rs1052501, rs2285803, rs4487645, and 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.
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany;
Niels
N
Weinhold
David C
DC
Johnson
Andrew C
AC
Rawstron
Asta
A
Försti
Chi
C
Doughty
Jayaram
J
Vijayakrishnan
Peter
P
Broderick
Nasrin B
NB
Dahir
Dil B
DB
Begum
Fay J
FJ
Hosking
Kwee
K
Yong
Brian A
BA
Walker
Per
P
Hoffmann
Thomas W
TW
Mühleisen
Christian
C
Langer
Elisabeth
E
Dörner
Karl-Heinz
KH
Jöckel
Lewin
L
Eisele
Markus M
MM
Nöthen
Dirk
D
Hose
Faith E
FE
Davies
Hartmut
H
Goldschmidt
Gareth J
GJ
Morgan
Kari
K
Hemminki
Richard S
RS
Houlston
D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D009101:Multiple Myeloma / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide