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

M. I. Da Silva Filho, A. Försti, N. Weinhold, I. Meziane, C. Campo, S. Huhn, J. Nickel, P. Hoffmann, M. M. Nöthen, K. H. Jöckel, S. Landi, J. S. Mitchell, D. Johnson, G. J. Morgan, R. Houlston, H. Goldschmidt, A. Jauch, P. Milani, G. Merlini, D. RowcienoP. Hawkins, U. Hegenbart, G. Palladini, A. Wechalekar, S. O. Schönland, K. Hemminki

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1735-1742
Number of pages8
JournalLeukemia
Volume31
Issue number8
DOIs
Publication statusPublished - Aug 1 2017

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ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Da Silva Filho, M. I., Försti, A., Weinhold, N., Meziane, I., Campo, C., Huhn, S., Nickel, J., Hoffmann, P., Nöthen, M. M., Jöckel, K. H., Landi, S., Mitchell, J. S., Johnson, D., Morgan, G. J., Houlston, R., Goldschmidt, H., Jauch, A., Milani, P., Merlini, G., ... Hemminki, K. (2017). Genome-wide association study of immunoglobulin light chain amyloidosis in three patient cohorts: Comparison with myeloma. Leukemia, 31(8), 1735-1742. https://doi.org/10.1038/leu.2016.387