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ULK4 and CDKN2A polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance

Sánchez-Maldonado, José Manuel ; Macauda, Angelica ; Cabrera-Serrano, Antonio José ; Thomsen, Hauke LU orcid ; Güler, Murat ; Horst, Rob Ter ; van Guelpen, Bethany ; Vodicka, Pavel ; Landi, Stefano and Chattopadhyay, Subhayan LU orcid , et al. (2026) In International Journal of Cancer p.1-13
Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy-related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy-related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood-derived immune cell subsets and 103 circulating immunological proteins. Meta-analysis revealed a genome-wide significant association between the... (More)

Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy-related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy-related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood-derived immune cell subsets and 103 circulating immunological proteins. Meta-analysis revealed a genome-wide significant association between the ULK4rs6599175C allele and increased MGUS risk (p = 3.35 × 10−8). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p =.0038 and p =.0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p =.0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B-cell differentiation. Additionally, the CDKN2Ars2811710 variant showed a suggestive association with MGUS risk (p = 2.17 × 10−4), affecting transcription factor binding involved in B-cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome-wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B-cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
autophagy, blood-derived cell populations, genetic variants, MGUS, susceptibility
in
International Journal of Cancer
pages
1 - 13
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105032794538
  • pmid:41813586
ISSN
0020-7136
DOI
10.1002/ijc.70427
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2026 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
id
17191d7c-3eca-410c-b503-647e1b24c8d8
date added to LUP
2026-03-22 09:33:22
date last changed
2026-03-24 03:14:00
@article{17191d7c-3eca-410c-b503-647e1b24c8d8,
  abstract     = {{<p>Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy-related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy-related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood-derived immune cell subsets and 103 circulating immunological proteins. Meta-analysis revealed a genome-wide significant association between the ULK4<sub>rs6599175C</sub> allele and increased MGUS risk (p = 3.35 × 10<sup>−8</sup>). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p =.0038 and p =.0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p =.0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B-cell differentiation. Additionally, the CDKN2A<sub>rs2811710</sub> variant showed a suggestive association with MGUS risk (p = 2.17 × 10<sup>−4</sup>), affecting transcription factor binding involved in B-cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome-wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B-cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.</p>}},
  author       = {{Sánchez-Maldonado, José Manuel and Macauda, Angelica and Cabrera-Serrano, Antonio José and Thomsen, Hauke and Güler, Murat and Horst, Rob Ter and van Guelpen, Bethany and Vodicka, Pavel and Landi, Stefano and Chattopadhyay, Subhayan and Ünal, Pelin and Ruiz-Durán, Lucía and Casabonne, Delphine and Goldschmidt, Hartmut and Serin, Istemi and Carretero-Fernández, María and Cabezudo, Elena and Reyes-Zurita, Fernando and Norman, Aaron D. and García-Sanz, Ramón and Capurso, Gabriele and Hoffmann, Per and Pettersson-Kymmer, Ulrika and Jiménez-Romera, Francisco and Rajkumar, S. Vincent and Weinhold, Niels and Vodickova, Ludmila and Langer, Christian and Stein, Angelika and Karismaz, Abdulkadir and Moreno, Victor and Nöthen, Markus M. and Jöckel, Karl Heinz and Tavano, Francesca and Martínez-López, Joaquín and Kumar, Shaji K. and Gutiérrez-Bautista, Juan Francisco and Basso, Daniela and Späth, Florentin and Benavente, Yolanda and Hildebrandt, Michelle A.T. and Schmidt, Börge and Sevcikova, Tereza and Reis, Rui Manuel Vieira and Li, Yang and López-Nevot, Miguel Ángel and Netea, Mihai G. and Campa, Daniele and Clay-Gilmour, Alyssa and Slager, Susan L. and Hemminki, Kari and Vachon, Celine M. and Försti, Asta and Canzian, Federico and Sainz, Juan}},
  issn         = {{0020-7136}},
  keywords     = {{autophagy; blood-derived cell populations; genetic variants; MGUS; susceptibility}},
  language     = {{eng}},
  pages        = {{1--13}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{International Journal of Cancer}},
  title        = {{ULK4 and CDKN2A polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance}},
  url          = {{http://dx.doi.org/10.1002/ijc.70427}},
  doi          = {{10.1002/ijc.70427}},
  year         = {{2026}},
}