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A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

ABSTRACT: Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0.81, 95% confidence interval (95% CI) = 0.76-0.86, P(combined) = 3.5 × 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.

SUBMITTER: Cozen W

PROVIDER: S-EPMC4055950 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

Cozen W W Timofeeva M N MN Li D D Diepstra A A Hazelett D D Delahaye-Sourdeix M M Edlund C K CK Franke L L Rostgaard K K Van Den Berg D J DJ Cortessis V K VK Smedby K E KE Glaser S L SL Westra H-J HJ Robison L L LL Mack T M TM Ghesquieres H H Hwang A E AE Nieters A A de Sanjose S S Lightfoot T T Becker N N Maynadie M M Foretova L L Roman E E Benavente Y Y Rand K A KA Nathwani B N BN Glimelius B B Staines A A Boffetta P P Link B K BK Kiemeney L L Ansell S M SM Bhatia S S Strong L C LC Galan P P Vatten L L Habermann T M TM Duell E J EJ Lake A A Veenstra R N RN Visser L L Liu Y Y Urayama K Y KY Montgomery D D Gaborieau V V Weiss L M LM Byrnes G G Lathrop M M Cocco P P Best T T Skol A D AD Adami H-O HO Melbye M M Cerhan J R JR Gallagher A A Taylor G M GM Slager S L SL Brennan P P Coetzee G A GA Conti D V DV Onel K K Jarrett R F RF Hjalgrim H H van den Berg A A McKay J D JD

Nature communications 20140612

Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR)=0 ...[more]

PMID: 24920014

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Project description:OBJECTIVE:Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes. METHODS:Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis. RESULTS:Meta-analysis showed evidence of association (P < 1 × 10-6 ) at 9 regions: PRR9_LOR (P = 5.12 × 10-8 ), ILDR1_CD86 (P = 6.73 × 10-8 ), WDFY4 (P = 1.79 × 10-7 ), PTH1R (P = 1.87 × 10-7 ), RNF215 (P = 3.09 × 10-7 ), AHI1_LINC00271 (P = 3.48 × 10-7 ), JAK1 (P = 4.18 × 10-7 ), LINC00951 (P = 5.80 × 10-7 ), and HBP1 (P = 7.29 × 10-7 ). Of these, PRR9_LOR, ILDR1_CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22. CONCLUSION:This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA.

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A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

Publications

A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus.

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