title: Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma.
abstract: Immunoglobulin light chain (AL) amyloidosis is characterized by tissue deposition of amyloid fibers derived from immunoglobulin light chain. AL amyloidosis and multiple myeloma (MM) originate from monoclonal gammopathy of undetermined significance. We wanted to characterize germline susceptibility to AL amyloidosis using a genome-wide association study (GWAS) on 1229 AL amyloidosis patients from Germany, UK and Italy, and 7526 healthy local controls. For comparison with MM, recent GWAS data on 3790 cases were used. For AL amyloidosis, single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at P<10-5with homogeneity of results from the 3 sample sets; some of these were previously documented to influence MM risk, including the SNP at the IRF4 binding site. In AL amyloidosis, rs9344 at the splice site of cyclin D1, promoting translocation (11;14), reached the highest significance, P=7.80 × 10-11; the SNP was only marginally significant in MM. SNP rs79419269 close to gene SMARCD3 involved in chromatin remodeling was also significant (P=5.2 × 10-8). These data provide evidence for common genetic susceptibility to AL amyloidosis and MM. Cyclin D1 is a more prominent driver in AL amyloidosis than in MM, but the links to aggregation of light chains need to be demonstrated.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M I
authors.initials: MI
authors.lastname: da Silva Filho
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmo, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Försti
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: N
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Meziane
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Campo
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Huhn
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Nickel
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|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 and Brain Research Center, University of Bonn, Bonn, Germany.
authors.forename: M M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Germany.
authors.forename: K-H
authors.initials: KH
authors.lastname: Jöckel
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Landi
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Mitchell
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, Surrey, UK.
authors.forename: D
authors.identifier: 0000-0003-0887-3343
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey, UK.|Division of Molecular Pathology, The Institute of Cancer Research, Surrey, UK.
authors.forename: R
authors.initials: R
authors.lastname: Houlston
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|National Centre of Tumor Diseases, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Department of Molecular Medicine, Amyloidosis Research and Treatment Center, Foundation 'Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo', University of Pavia, Pavia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Milani
authors.affiliation: Department of Molecular Medicine, Amyloidosis Research and Treatment Center, Foundation 'Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo', University of Pavia, Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Merlini
authors.affiliation: National Amyloidosis Centre, University College London Medical School, London UK.
authors.forename: D
authors.initials: D
authors.lastname: Rowcieno
authors.affiliation: National Amyloidosis Centre, University College London Medical School, London UK.
authors.forename: P
authors.initials: P
authors.lastname: Hawkins
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Hegenbart
authors.affiliation: Department of Molecular Medicine, Amyloidosis Research and Treatment Center, Foundation 'Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo', University of Pavia, Pavia, Italy.
authors.forename: G
authors.identifier: 0000-0001-5994-5138
authors.initials: G
authors.lastname: Palladini
authors.affiliation: National Amyloidosis Centre, University College London Medical School, London UK.
authors.forename: A
authors.initials: A
authors.lastname: Wechalekar
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: S O
authors.initials: SO
authors.lastname: Schönland
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmo, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Hemminki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000686:Amyloidosis / Q000235:genetics*; D019938:Cyclin D1 / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D007147:Immunoglobulin Light Chains; D019938:Cyclin D1