Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis,...
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Published in | International journal of molecular sciences Vol. 24; no. 10; p. 8500 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
MDPI AG
09.05.2023
MDPI |
Subjects | |
Online Access | Get full text |
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Summary: | Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs;
< 1 × 10
) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci,
,
,
,
,
, and
associated with MM risk (
= 4.47 × 10
-5.79 × 10
). Mechanistically, we found that the
SNP correlated with circulating concentrations of vitamin D3 (
= 4.0 × 10
), whereas the
SNP correlated with the number of transitional CD24
CD38
B cells (
= 4.8 × 10
) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (
= 3.6 × 10
). We also found that the
SNP correlated with numbers of CD19
B cells, CD19
CD3
B cells, CD5
IgD
cells, IgM
cells, IgD
IgM
cells, and CD4
CD8
PBMCs (
= 4.9 × 10
-8.6 × 10
) and circulating concentrations of interleukin (IL)-20 (
= 0.00082). Finally, we observed that the
SNP correlated with levels of CD4
EMCD45RO
CD27
cells (
= 9.3 × 10
). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3
, MCP-2
, and IL20-dependent pathways. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 These authors contributed equally to this work. |
ISSN: | 1422-0067 1661-6596 1422-0067 |
DOI: | 10.3390/ijms24108500 |