Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

Geffen Kleinstern; Huihuang Yan; Michelle A.T. Hildebrandt; Joseph Vijai; Sonja I. Berndt; Hervé Ghesquières; James McKay; Sophia S. Wang; Alexandra Nieters; Yuanqing Ye; Alain Monnereau; Angela R. Brooks-Wilson; Qing Lan; Mads Melbye; Rebecca D. Jackson; Lauren R. Teras; Mark P. Purdue; Claire M. Vajdic; Roel C.H. Vermeulen; Graham G. Giles; Pier Luigi Cocco; Brenda M. Birmann; Peter Kraft; Demetrius Albanes; Anne Zeleniuch-Jacquotte; Simon Crouch; Yawei Zhang; Vivekananda Sarangi; Yan Asmann; Kenneth Offit; Gilles Salles; Xifeng Wu; Karin E. Smedby; Christine F. Skibola; Susan L. Slager; Nathaniel Rothman; Stephen J. Chanock; James R. Cerhan

doi:10.1093/hmg/ddz228

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

Geffen Kleinstern, Huihuang Yan, Michelle A.T. Hildebrandt, Joseph Vijai, Sonja I. Berndt, Hervé Ghesquières, James McKay, Sophia S. Wang, Alexandra Nieters, Yuanqing Ye, Alain Monnereau, Angela R. Brooks-Wilson, Qing Lan, Mads Melbye, Rebecca D. Jackson, Lauren R. Teras, Mark P. Purdue, Claire M. Vajdic, Roel C.H. Vermeulen, Graham G. GilesPier Luigi Cocco, Brenda M. Birmann, Peter Kraft, Demetrius Albanes, Anne Zeleniuch-Jacquotte, Simon Crouch, Yawei Zhang, Vivekananda Sarangi, Yan Asmann, Kenneth Offit, Gilles Salles, Xifeng Wu, Karin E. Smedby, Christine F. Skibola, Susan L. Slager, Nathaniel Rothman, Stephen J. Chanock, James R. Cerhan

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

Abstract

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10^-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10^-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Original language	American English
Pages (from-to)	70-79
Number of pages	10
Journal	Human Molecular Genetics
Volume	29
Issue number	1
DOIs	https://doi.org/10.1093/hmg/ddz228
State	Published - 1 Jan 2020
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/hmg/ddz228

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Kleinstern, G., Yan, H., Hildebrandt, M. A. T., Vijai, J., Berndt, S. I., Ghesquières, H., McKay, J., Wang, S. S., Nieters, A., Ye, Y., Monnereau, A., Brooks-Wilson, A. R., Lan, Q., Melbye, M., Jackson, R. D., Teras, L. R., Purdue, M. P., Vajdic, C. M., Vermeulen, R. C. H., ... Cerhan, J. R. (2020). Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways. Human Molecular Genetics, 29(1), 70-79. https://doi.org/10.1093/hmg/ddz228

@article{640b838800894d45bc383a9a0f95451e,

title = "Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways",

abstract = "We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.",

author = "Geffen Kleinstern and Huihuang Yan and Hildebrandt, {Michelle A.T.} and Joseph Vijai and Berndt, {Sonja I.} and Herv{\'e} Ghesqui{\`e}res and James McKay and Wang, {Sophia S.} and Alexandra Nieters and Yuanqing Ye and Alain Monnereau and Brooks-Wilson, {Angela R.} and Qing Lan and Mads Melbye and Jackson, {Rebecca D.} and Teras, {Lauren R.} and Purdue, {Mark P.} and Vajdic, {Claire M.} and Vermeulen, {Roel C.H.} and Giles, {Graham G.} and Cocco, {Pier Luigi} and Birmann, {Brenda M.} and Peter Kraft and Demetrius Albanes and Anne Zeleniuch-Jacquotte and Simon Crouch and Yawei Zhang and Vivekananda Sarangi and Yan Asmann and Kenneth Offit and Gilles Salles and Xifeng Wu and Smedby, {Karin E.} and Skibola, {Christine F.} and Slager, {Susan L.} and Nathaniel Rothman and Chanock, {Stephen J.} and Cerhan, {James R.}",

year = "2020",

month = jan,

day = "1",

doi = "10.1093/hmg/ddz228",

language = "American English",

volume = "29",

pages = "70--79",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "1",

}

Kleinstern, G, Yan, H, Hildebrandt, MAT, Vijai, J, Berndt, SI, Ghesquières, H, McKay, J, Wang, SS, Nieters, A, Ye, Y, Monnereau, A, Brooks-Wilson, AR, Lan, Q, Melbye, M, Jackson, RD, Teras, LR, Purdue, MP, Vajdic, CM, Vermeulen, RCH, Giles, GG, Cocco, PL, Birmann, BM, Kraft, P, Albanes, D, Zeleniuch-Jacquotte, A, Crouch, S, Zhang, Y, Sarangi, V, Asmann, Y, Offit, K, Salles, G, Wu, X, Smedby, KE, Skibola, CF, Slager, SL, Rothman, N, Chanock, SJ & Cerhan, JR 2020, 'Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways', Human Molecular Genetics, vol. 29, no. 1, pp. 70-79. https://doi.org/10.1093/hmg/ddz228

TY - JOUR

T1 - Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

AU - Kleinstern, Geffen

AU - Yan, Huihuang

AU - Hildebrandt, Michelle A.T.

AU - Vijai, Joseph

AU - Berndt, Sonja I.

AU - Ghesquières, Hervé

AU - McKay, James

AU - Wang, Sophia S.

AU - Nieters, Alexandra

AU - Ye, Yuanqing

AU - Monnereau, Alain

AU - Brooks-Wilson, Angela R.

AU - Lan, Qing

AU - Melbye, Mads

AU - Jackson, Rebecca D.

AU - Teras, Lauren R.

AU - Purdue, Mark P.

AU - Vajdic, Claire M.

AU - Vermeulen, Roel C.H.

AU - Giles, Graham G.

AU - Cocco, Pier Luigi

AU - Birmann, Brenda M.

AU - Kraft, Peter

AU - Albanes, Demetrius

AU - Zeleniuch-Jacquotte, Anne

AU - Crouch, Simon

AU - Zhang, Yawei

AU - Sarangi, Vivekananda

AU - Asmann, Yan

AU - Offit, Kenneth

AU - Salles, Gilles

AU - Wu, Xifeng

AU - Smedby, Karin E.

AU - Skibola, Christine F.

AU - Slager, Susan L.

AU - Rothman, Nathaniel

AU - Chanock, Stephen J.

AU - Cerhan, James R.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

AB - We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

UR - http://www.scopus.com/inward/record.url?scp=85079019341&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddz228

DO - 10.1093/hmg/ddz228

M3 - Article

C2 - 31600786

SN - 0964-6906

VL - 29

SP - 70

EP - 79

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 1

ER -

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

Abstract

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