TY  - JOUR
AU  - Clavero, Esther
AU  - Sanchez-Maldonado, José Manuel
AU  - Macauda, Angelica
AU  - Ter Horst, Rob
AU  - Sampaio-Marques, Belém
AU  - Jurczyszyn, Artur
AU  - Clay-Gilmour, Alyssa
AU  - Stein, Angelika
AU  - Hildebrandt, Michelle A T
AU  - Weinhold, Niels
AU  - Buda, Gabriele
AU  - García-Sanz, Ramón
AU  - Tomczak, Waldemar
AU  - Vogel, Ulla
AU  - Jerez, Andrés
AU  - Zawirska, Daria
AU  - Wątek, Marzena
AU  - Hofmann, Jonathan N
AU  - Landi, Stefano
AU  - Spinelli, John J
AU  - Butrym, Aleksandra
AU  - Kumar, Abhishek
AU  - Martínez-López, Joaquín
AU  - Galimberti, Sara
AU  - Sarasquete, María Eugenia
AU  - Subocz, Edyta
AU  - Iskierka-Jażdżewska, Elzbieta
AU  - Giles, Graham G
AU  - Rybicka-Ramos, Malwina
AU  - Kruszewski, Marcin
AU  - Abildgaard, Niels
AU  - Verdejo, Francisco García
AU  - Sánchez Rovira, Pedro
AU  - da Silva Filho, Miguel Inacio
AU  - Kadar, Katalin
AU  - Razny, Małgorzata
AU  - Cozen, Wendy
AU  - Pelosini, Matteo
AU  - Jurado, Manuel
AU  - Bhatti, Parveen
AU  - Dudzinski, Marek
AU  - Druzd-Sitek, Agnieszka
AU  - Orciuolo, Enrico
AU  - Li, Yang
AU  - Norman, Aaron D
AU  - Zaucha, Jan Maciej
AU  - Reis, Rui Manuel
AU  - Markiewicz, Miroslaw
AU  - Rodríguez Sevilla, Juan José
AU  - Andersen, Vibeke
AU  - Jamroziak, Krzysztof
AU  - Hemminki, Kari
AU  - Berndt, Sonja I
AU  - Rajkumar, Vicent
AU  - Mazur, Grzegorz
AU  - Kumar, Shaji K
AU  - Ludovico, Paula
AU  - Nagler, Arnon
AU  - Chanock, Stephen J
AU  - Dumontet, Charles
AU  - Machiela, Mitchell J
AU  - Varkonyi, Judit
AU  - Camp, Nicola J
AU  - Ziv, Elad
AU  - Vangsted, Annette Juul
AU  - Brown, Elizabeth E
AU  - Campa, Daniele
AU  - Vachon, Celine M
AU  - Netea, Mihai G
AU  - Canzian, Federico
AU  - Försti, Asta
AU  - Sainz, Juan
TI  - Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.
JO  - International journal of molecular sciences
VL  - 24
IS  - 10
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2023-01054
SP  - 8500
PY  - 2023
AB  - 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; p < 1 × 10-9) 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, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). 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.
KW  - Humans
KW  - Multiple Myeloma: genetics
KW  - Multiple Myeloma: pathology
KW  - Leukocytes, Mononuclear: pathology
KW  - Biomarkers
KW  - Immunoglobulin M
KW  - Autophagy
KW  - autophagy (Other)
KW  - genetic susceptibility (Other)
KW  - genetic variants (Other)
KW  - multiple myeloma (Other)
KW  - Biomarkers (NLM Chemicals)
KW  - Immunoglobulin M (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37239846
C2  - pmc:PMC10218542
DO  - DOI:10.3390/ijms24108500
UR  - https://inrepo02.dkfz.de/record/276324
ER  -