Sequencing at lymphoid neoplasm susceptibility loci maps six myeloma risk genes.

Acyl-CoA Oxidase / genetics Butyrophilins / genetics Female Genetic Predisposition to Disease Genome-Wide Association Study Hodgkin Disease / genetics Humans Interferon Regulatory Factors / genetics Leukemia, Lymphocytic, Chronic, B-Cell / genetics Lymphocytes / pathology Lymphoma, Follicular / genetics Lymphoma, Large B-Cell, Diffuse / genetics Male Multiple Myeloma / genetics Polymorphism, Single Nucleotide / genetics Risk Factors T-Box Domain Proteins / genetics Tetraspanins / genetics Transmembrane Activator and CAML Interactor Protein / genetics Exome Sequencing

Journal

Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958

Informations de publication

Date de publication:
09 06 2021
Historique:
received: 16 11 2020
revised: 22 02 2021
accepted: 23 02 2021
pubmed: 23 3 2021
medline: 8 3 2022
entrez: 22 3 2021
Statut: ppublish

Résumé

Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10-6), EOMES (P = 6.0 × 10-6) and BTNL2 (P = 2.1 × 10-3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.

Identifiants

DOI: 10.1093/hmg/ddab066 PMID: 33751038 PMC: PMC8188404
pubmed: 33751038
pii: 6159376
doi: 10.1093/hmg/ddab066
pmc: PMC8188404
doi:

Substances chimiques

BTNL2 protein, human 0
Butyrophilins 0
EOMES protein, human 0
Interferon Regulatory Factors 0
T-Box Domain Proteins 0
TNFRSF13B protein, human 0
TSPAN32 protein, human 0
Tetraspanins 0
Transmembrane Activator and CAML Interactor Protein 0
interferon regulatory factor-8 0
ACOXL protein, human EC 1.3.3.6
Acyl-CoA Oxidase EC 1.3.3.6

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

1142-1153

Subventions

Organisme : NHLBI NIH HHS
ID : RC2 HL102923
Pays : United States
Organisme : NHLBI NIH HHS
ID : RC2 HL102926
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95169
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95162
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95168
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA167824
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95165
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95159
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95161
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95166
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95160
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA209533
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR025005
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95163
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800016C
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95164
Pays : United States
Organisme : NHLBI NIH HHS
ID : RC2 HL102924
Pays : United States
Organisme : NCI NIH HHS
ID : F99 CA234943
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA234943
Pays : United States
Organisme : NHLBI NIH HHS
ID : N01HC95167
Pays : United States
Organisme : NHLBI NIH HHS
ID : RC2 HL103010
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000040
Pays : United States
Organisme : NHLBI NIH HHS
ID : RC2 HL102925
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA042014
Pays : United States

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Auteurs

Rosalie Griffin Waller (RG)

Department of Biomedical Informatics, University of Utah, Salt Lake City, UT 84112, USA.

Robert J Klein (RJ)

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Icahn Institute for Data Science and Genomic Technology, New York, NY 10029-5674, USA.

Joseph Vijai (J)

Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

James D McKay (JD)

Genetic Cancer Susceptibility, International Agency for Research on Cancer, 69372 Lyon Cedex 08, France.

Alyssa Clay-Gilmour (A)

Department of Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.

Xiaomu Wei (X)

Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

Michael J Madsen (MJ)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Douglas W Sborov (DW)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Karen Curtin (K)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Susan L Slager (SL)

Department of Health Sciences, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.

Kenneth Offit (K)

Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

Celine M Vachon (CM)

Department of Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN 55905, USA.

Steven M Lipkin (SM)

Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.

Charles Dumontet (C)

INSERM 1052, CNRS 5286, University of Lyon, 69361 Lyon Cedex 07, France.

Nicola J Camp (NJ)

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Flavoprotéines › Acyl-CoA oxidase › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Glycoprotéines membranaires › Butyrophilines › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Maladie de Hodgkin › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de régulation d'interféron › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Leucémie chronique lymphocytaire à cellules B › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome folliculaire › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Syndromes lymphoprolifératifs › Lymphomes › Lymphome malin non hodgkinien › Lymphome B › Lymphome B diffus à grandes cellules › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Paraprotéinémies › Myélome multiple › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines à domaine boîte-T › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Tétraspanines › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs aux cytokines › Récepteurs aux facteurs de nécrose tumorale › Protéine TACI › Sequencing at lymphoid neoplasm susceptibility...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › Sequencing at lymphoid neoplasm susceptibility...