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Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility.

ABSTRACT: Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P?=?1.52?×?10-8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P?=?9.43?×?10-17), 6q23.3 (rs6928977, P?=?4.62?×?10-11), 10p14 (rs3781093, P?=?9.49?×?10-13), 13q34 (rs112998813, P?=?4.58?×?10-8) and 16p13.13 (rs34972832, P?=?2.12?×?10-8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.

SUBMITTER: Sud A

PROVIDER: S-EPMC5711884 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility.

Sud Amit A Thomsen Hauke H Law Philip J PJ Försti Asta A Filho Miguel Inacio da Silva MIDS Holroyd Amy A Broderick Peter P Orlando Giulia G Lenive Oleg O Wright Lauren L Cooke Rosie R Easton Douglas D Pharoah Paul P Dunning Alison A Peto Julian J Canzian Federico F Eeles Rosalind R Kote-Jarai ZSofia Z Muir Kenneth K Pashayan Nora N Hoffmann Per P Nöthen Markus M MM Jöckel Karl-Heinz KH Strandmann Elke Pogge von EPV Lightfoot Tracy T Kane Eleanor E Roman Eve E Lake Annette A Montgomery Dorothy D Jarrett Ruth F RF Swerdlow Anthony J AJ Engert Andreas A Orr Nick N Hemminki Kari K Houlston Richard S RS

Nature communications 20171201 1

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10<sup>-8</sup>) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10<sup>-17</s ...[more]

PMID: 29196614

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Project description:BackgroundAccumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification.MethodsWe conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided.ResultsTwo novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03).ConclusionOverall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.

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Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility.

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Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility.

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