title: Genetic factors influencing the risk of multiple myeloma bone disease.
abstract: A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.|Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Mitchell
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: O W
authors.initials: OW
authors.lastname: Stephens
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Försti
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Nickel
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Leeds Institute of Molecular Medicine, Section of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: W A
authors.initials: WA
authors.lastname: Gregory
authors.affiliation: Leeds Institute of Molecular Medicine, Section of Clinical Trials Research, University of Leeds, Leeds, UK.
authors.forename: D
authors.identifier: http://orcid.org/0000-0002-2338-0179
authors.initials: D
authors.lastname: Cairns
authors.affiliation: Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, UK.
authors.forename: G H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Noethen
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hillengass
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Bertsch
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: B
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Davis
authors.affiliation: German Cancer Research Center, Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|National Center of Tumor Diseases, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, UK.|Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: R S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Morgan
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001847:Bone Diseases / Q000209:etiology* / Q000473:pathology; D005260:Female; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000235:genetics*; D009367:Neoplasm Staging; D053244:Osteoprotegerin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human