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Multiple Myeloma, Gammopathies

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

Leukemia volume 31, pages 1735–1742 (2017)Cite this article

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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<10−5 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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Acknowledgements

Funding was provided by the German Cancer Aid, the Harald Huppert Foundations, The German Federal Ministry of Education and Research (eMed, Cliommics 01ZX1309B), the Multiple Myeloma Research Foundation, the Heinz Nixdorf Foundation (Germany), the Ministerium für Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen and the Faculty of Medicine University Duisburg-Essen. In the UK Myeloma UK and Bloodwise provided principal funding. Additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and The Rosetrees Trust. This study made use of genotyping data on the 1958 Birth Cohort generated by the Wellcome Trust Sanger Institute (http://www.wtccc.org.uk).

Author information

Author notes

  1. M I da Silva Filho, A Försti and N Weinhold: Shared first authorship.

  2. S O Schönland and K Hemminki: Shared last authorship.

Authors and Affiliations

  1. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    M I da Silva Filho, A Försti, I Meziane, C Campo & K Hemminki

  2. Center for Primary Health Care Research, Lund University, Malmo, Sweden

    A Försti & K Hemminki

  3. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    N Weinhold, S Huhn, J Nickel, H Goldschmidt, U Hegenbart & S O Schönland

  4. Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    N Weinhold & G J Morgan

  5. Institute of Human Genetics, University of Bonn, Bonn, Germany

    P Hoffmann & M M Nöthen

  6. Department of Biomedicine, University of Basel, Basel, Switzerland

    P Hoffmann

  7. Department of Genomics, Life and Brain Research Center, University of Bonn, Bonn, Germany

    M M Nöthen

  8. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Germany

    K-H Jöckel

  9. Department of Biology, University of Pisa, Pisa, Italy

    S Landi

  10. Division of Genetics and Epidemiology, The Institute of Cancer Research, Surrey, UK

    J S Mitchell & R Houlston

  11. Division of Molecular Pathology, The Institute of Cancer Research, Surrey, UK

    D Johnson & R Houlston

  12. National Centre of Tumor Diseases, Heidelberg, Germany

    H Goldschmidt

  13. Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany

    A Jauch

  14. 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

    P Milani, G Merlini & G Palladini

  15. National Amyloidosis Centre, University College London Medical School, London, UK

    D Rowcieno, P Hawkins & A Wechalekar

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  1. M I da Silva Filho
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  2. A Försti
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Correspondence to K Hemminki.

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da Silva Filho, M., Försti, A., Weinhold, N. et al. Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: comparison with myeloma. Leukemia 31, 1735–1742 (2017). https://doi.org/10.1038/leu.2016.387

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