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Search for AL amyloidosis risk factors using Mendelian randomization

Saunders, Charlie N. ; Chattopadhyay, Subhayan LU orcid ; Huhn, Stefanie ; Weinhold, Niels ; Hoffmann, Per ; Nöthen, Markus M. ; Jöckel, Karl Heinz ; Schmidt, Börge ; Landi, Stefano and Goldschmidt, Hartmut , et al. (2021) In Blood Advances 5(13). p.2725-2731
Abstract

In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencingALamyloidosis risk.Weperformed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis... (More)

In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencingALamyloidosis risk.Weperformed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.

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type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
5
issue
13
pages
7 pages
publisher
American Society of Hematology
external identifiers
  • pmid:34228109
  • scopus:85110153087
ISSN
2473-9529
DOI
10.1182/bloodadvances.2021004423
language
English
LU publication?
yes
additional info
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dfc1388b-3846-4d9a-9fdd-0fc585716f11
date added to LUP
2022-03-08 11:21:21
date last changed
2024-03-17 05:56:52
@article{dfc1388b-3846-4d9a-9fdd-0fc585716f11,
  abstract     = {{<p>In amyloid light chain (AL) amyloidosis, amyloid fibrils derived from immunoglobulin light chain are deposited in many organs, interfering with their function. The etiology of AL amyloidosis is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited by Mendelian randomization (MR) methodology to search for factors influencingALamyloidosis risk.Weperformed a 2-sample MR analyzing 72 phenotypes, proxied by 3461 genetic variants, and summary genetic data from a GWAS of 1129 AL amyloidosis cases and 7589 controls. Associations with a Bonferroni-defined significance level were observed for genetically predicted increased monocyte counts (P = 3.8 × 10-4) and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17) gene (P = 3.4 × 10-5). Two other associations with the TNFRSF (members 6 and 19L) reached a nominal significance level. The association between genetically predicted decreased fibrinogen levels may be related to roles of fibrinogen other than blood clotting. be related to its nonhemostatic role. It is plausible that a causal relationship with monocyte concentration could be explained by selection of a light chain-producing clone during progression of monoclonal gammopathy of unknown significance toward AL amyloidosis. Because TNFRSF proteins have key functions in lymphocyte biology, it is entirely plausible that they offer a potential link to AL amyloidosis pathophysiology. Our study provides insight into AL amyloidosis etiology, suggesting high circulating levels of monocytes and TNFRSF proteins as risk factors.</p>}},
  author       = {{Saunders, Charlie N. and Chattopadhyay, Subhayan and Huhn, Stefanie and Weinhold, Niels and Hoffmann, Per and Nöthen, Markus M. and Jöckel, Karl Heinz and Schmidt, Börge and Landi, Stefano and Goldschmidt, Hartmut and Milani, Paolo and Merlini, Giampaolo and Rowcieno, Dorota and Hawkins, Philip and Hegenbart, Ute and Palladini, Giovanni and Wechalekar, Ashutosh and Schönland, Stefan O. and Försti, Asta and Houlston, Richard and Hemminki, Kari}},
  issn         = {{2473-9529}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{13}},
  pages        = {{2725--2731}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{Search for AL amyloidosis risk factors using Mendelian randomization}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2021004423}},
  doi          = {{10.1182/bloodadvances.2021004423}},
  volume       = {{5}},
  year         = {{2021}},
}