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Leukemia. 2017 Aug;31(8):1735-1742. doi: 10.1038/leu.2016.387. Epub 2016 Dec 27.

Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma.

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Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Center for Primary Health Care Research, Lund University, Malmo, Sweden.
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany.
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Germany.
Department of Biology, University of Pisa, Pisa, Italy.
Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey, UK.
Division of Molecular Pathology, The Institute of Cancer Research, Surrey, UK.
National Centre of Tumor Diseases, Heidelberg, Germany.
Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
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.
National Amyloidosis Centre, University College London Medical School, London UK.


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<10-5 with 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.

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