A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

Marco Dicanio; Matteo Giaccherini; Alyssa Clay-Gilmour; Angelica Macauda; Juan Sainz; Mitchell J. Machiela; Malwina Rybicka-Ramos; Aaron D. Norman; Agata Tyczyńska; Stephen J. Chanock; Torben Barington; Shaji K. Kumar; Parveen Bhatti; Wendy Cozen; Elizabeth E. Brown; Anna Suska; Eva K. Haastrup; Robert Z. Orlowski; Marek Dudziński; Ramon Garcia-Sanz; Marcin Kruszewski; Joaquin Martinez-Lopez; Katia Beider; Elżbieta Iskierka-Jazdzewska; Matteo Pelosini; Sonja I. Berndt; Małgorzata Raźny; Krzysztof Jamroziak; S. Vincent Rajkumar; Artur Jurczyszyn; Annette Juul Vangsted; Pilar Garrido Collado; Ulla Vogel; Jonathan N. Hofmann; Mario Petrini; Aleksandra Butrym; Susan L. Slager; Elad Ziv; Edyta Subocz; Graham G. Giles; Niels Frost Andersen; Grzegorz Mazur; Marzena Watek; Fabienne Lesueur; Michelle A.T. Hildebrandt; Daria Zawirska; Lene Hyldahl Ebbesen; Herlander Marques; Federica Gemignani; Charles Dumontet; Judit Várkonyi; Gabriele Buda; Arnon Nagler; Agnieszka Druzd-Sitek; Xifeng Wu; Katalin Kadar; Nicola J. Camp; Norbert Grzasko; Rosalie G. Waller; Celine Vachon; Federico Canzian; Daniele Campa

doi:10.1002/ijc.34278

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

Marco Dicanio, Matteo Giaccherini, Alyssa Clay-Gilmour, Angelica Macauda, Juan Sainz, Mitchell J. Machiela, Malwina Rybicka-Ramos, Aaron D. Norman, Agata Tyczyńska, Stephen J. Chanock, Torben Barington, Shaji K. Kumar, Parveen Bhatti, Wendy Cozen, Elizabeth E. Brown, Anna Suska, Eva K. Haastrup, Robert Z. Orlowski, Marek Dudziński, Ramon Garcia-SanzMarcin Kruszewski, Joaquin Martinez-Lopez, Katia Beider, Elżbieta Iskierka-Jazdzewska, Matteo Pelosini, Sonja I. Berndt, Małgorzata Raźny, Krzysztof Jamroziak, S. Vincent Rajkumar, Artur Jurczyszyn, Annette Juul Vangsted, Pilar Garrido Collado, Ulla Vogel, Jonathan N. Hofmann, Mario Petrini, Aleksandra Butrym, Susan L. Slager, Elad Ziv, Edyta Subocz, Graham G. Giles, Niels Frost Andersen, Grzegorz Mazur, Marzena Watek, Fabienne Lesueur, Michelle A.T. Hildebrandt, Daria Zawirska, Lene Hyldahl Ebbesen, Herlander Marques, Federica Gemignani, Charles Dumontet, Judit Várkonyi, Gabriele Buda, Arnon Nagler, Agnieszka Druzd-Sitek, Xifeng Wu, Katalin Kadar, Nicola J. Camp, Norbert Grzasko, Rosalie G. Waller, Celine Vachon, Federico Canzian, Daniele Campa

Research output: Contribution to journal › Article › peer-review

Abstract

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10⁻⁸) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10⁻⁷). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Original language	English (US)
Pages (from-to)	239-248
Number of pages	10
Journal	International Journal of Cancer
Volume	152
Issue number	2
DOIs	https://doi.org/10.1002/ijc.34278
State	Published - Jan 15 2023

Keywords

genetic susceptibility
multiple myeloma
pleiotropy
pleiotropy scan
polymorphisms

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1002/ijc.34278

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Dicanio, M., Giaccherini, M., Clay-Gilmour, A., Macauda, A., Sainz, J., Machiela, M. J., Rybicka-Ramos, M., Norman, A. D., Tyczyńska, A., Chanock, S. J., Barington, T., Kumar, S. K., Bhatti, P., Cozen, W., Brown, E. E., Suska, A., Haastrup, E. K., Orlowski, R. Z., Dudziński, M., ... Campa, D. (2023). A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk. International Journal of Cancer, 152(2), 239-248. https://doi.org/10.1002/ijc.34278

Dicanio, M, Giaccherini, M, Clay-Gilmour, A, Macauda, A, Sainz, J, Machiela, MJ, Rybicka-Ramos, M, Norman, AD, Tyczyńska, A, Chanock, SJ, Barington, T, Kumar, SK, Bhatti, P, Cozen, W, Brown, EE, Suska, A, Haastrup, EK, Orlowski, RZ, Dudziński, M, Garcia-Sanz, R, Kruszewski, M, Martinez-Lopez, J, Beider, K, Iskierka-Jazdzewska, E, Pelosini, M, Berndt, SI, Raźny, M, Jamroziak, K, Rajkumar, SV, Jurczyszyn, A, Vangsted, AJ, Collado, PG, Vogel, U, Hofmann, JN, Petrini, M, Butrym, A, Slager, SL, Ziv, E, Subocz, E, Giles, GG, Andersen, NF, Mazur, G, Watek, M, Lesueur, F, Hildebrandt, MAT, Zawirska, D, Ebbesen, LH, Marques, H, Gemignani, F, Dumontet, C, Várkonyi, J, Buda, G, Nagler, A, Druzd-Sitek, A, Wu, X, Kadar, K, Camp, NJ, Grzasko, N, Waller, RG, Vachon, C, Canzian, F & Campa, D 2023, 'A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk', International Journal of Cancer, vol. 152, no. 2, pp. 239-248. https://doi.org/10.1002/ijc.34278

@article{7472f20e701242a4af075a2320459243,

title = "A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk",

abstract = "Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.",

keywords = "genetic susceptibility, multiple myeloma, pleiotropy, pleiotropy scan, polymorphisms",

author = "Marco Dicanio and Matteo Giaccherini and Alyssa Clay-Gilmour and Angelica Macauda and Juan Sainz and Machiela, {Mitchell J.} and Malwina Rybicka-Ramos and Norman, {Aaron D.} and Agata Tyczy{\'n}ska and Chanock, {Stephen J.} and Torben Barington and Kumar, {Shaji K.} and Parveen Bhatti and Wendy Cozen and Brown, {Elizabeth E.} and Anna Suska and Haastrup, {Eva K.} and Orlowski, {Robert Z.} and Marek Dudzi{\'n}ski and Ramon Garcia-Sanz and Marcin Kruszewski and Joaquin Martinez-Lopez and Katia Beider and El{\.z}bieta Iskierka-Jazdzewska and Matteo Pelosini and Berndt, {Sonja I.} and Ma{\l}gorzata Ra{\'z}ny and Krzysztof Jamroziak and Rajkumar, {S. Vincent} and Artur Jurczyszyn and Vangsted, {Annette Juul} and Collado, {Pilar Garrido} and Ulla Vogel and Hofmann, {Jonathan N.} and Mario Petrini and Aleksandra Butrym and Slager, {Susan L.} and Elad Ziv and Edyta Subocz and Giles, {Graham G.} and Andersen, {Niels Frost} and Grzegorz Mazur and Marzena Watek and Fabienne Lesueur and Hildebrandt, {Michelle A.T.} and Daria Zawirska and Ebbesen, {Lene Hyldahl} and Herlander Marques and Federica Gemignani and Charles Dumontet and Judit V{\'a}rkonyi and Gabriele Buda and Arnon Nagler and Agnieszka Druzd-Sitek and Xifeng Wu and Katalin Kadar and Camp, {Nicola J.} and Norbert Grzasko and Waller, {Rosalie G.} and Celine Vachon and Federico Canzian and Daniele Campa",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",

year = "2023",

month = jan,

day = "15",

doi = "10.1002/ijc.34278",

language = "English (US)",

volume = "152",

pages = "239--248",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

number = "2",

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TY - JOUR

T1 - A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

AU - Dicanio, Marco

AU - Giaccherini, Matteo

AU - Clay-Gilmour, Alyssa

AU - Macauda, Angelica

AU - Sainz, Juan

AU - Machiela, Mitchell J.

AU - Rybicka-Ramos, Malwina

AU - Norman, Aaron D.

AU - Tyczyńska, Agata

AU - Chanock, Stephen J.

AU - Barington, Torben

AU - Kumar, Shaji K.

AU - Bhatti, Parveen

AU - Cozen, Wendy

AU - Brown, Elizabeth E.

AU - Suska, Anna

AU - Haastrup, Eva K.

AU - Orlowski, Robert Z.

AU - Dudziński, Marek

AU - Garcia-Sanz, Ramon

AU - Kruszewski, Marcin

AU - Martinez-Lopez, Joaquin

AU - Beider, Katia

AU - Iskierka-Jazdzewska, Elżbieta

AU - Pelosini, Matteo

AU - Berndt, Sonja I.

AU - Raźny, Małgorzata

AU - Jamroziak, Krzysztof

AU - Rajkumar, S. Vincent

AU - Jurczyszyn, Artur

AU - Vangsted, Annette Juul

AU - Collado, Pilar Garrido

AU - Vogel, Ulla

AU - Hofmann, Jonathan N.

AU - Petrini, Mario

AU - Butrym, Aleksandra

AU - Slager, Susan L.

AU - Ziv, Elad

AU - Subocz, Edyta

AU - Giles, Graham G.

AU - Andersen, Niels Frost

AU - Mazur, Grzegorz

AU - Watek, Marzena

AU - Lesueur, Fabienne

AU - Hildebrandt, Michelle A.T.

AU - Zawirska, Daria

AU - Ebbesen, Lene Hyldahl

AU - Marques, Herlander

AU - Gemignani, Federica

AU - Dumontet, Charles

AU - Várkonyi, Judit

AU - Buda, Gabriele

AU - Nagler, Arnon

AU - Druzd-Sitek, Agnieszka

AU - Wu, Xifeng

AU - Kadar, Katalin

AU - Camp, Nicola J.

AU - Grzasko, Norbert

AU - Waller, Rosalie G.

AU - Vachon, Celine

AU - Canzian, Federico

AU - Campa, Daniele

PY - 2023/1/15

Y1 - 2023/1/15

N2 - Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

AB - Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

KW - genetic susceptibility

KW - multiple myeloma

KW - pleiotropy

KW - pleiotropy scan

KW - polymorphisms

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U2 - 10.1002/ijc.34278

DO - 10.1002/ijc.34278

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C2 - 36082445

AN - SCOPUS:85139053286

SN - 0020-7136

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SP - 239

EP - 248

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 2

ER -

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

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