GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma.

Karin E Smedby,Bengt Glimelius,Lars Alfredsson,Zachary S Fredericksen,Hatef Darabi,Vikrant Kumar,Neil E Kay,James R Cerhan,Martyn T Smith,Jacques Riby,Anne J Novak,Scott Davis,Luz Agana,Ellen T Chang,Paige M Bracci,Thomas M Habermann,Henrik Hjalgrim,Peter N Brown,Wendy Cozen,Keith Humphreys,Stephen J Chanock,Lars Klareskog,Leonid Padyukov,Nathaniel Rothman,Jia Nee Foo,Peter Boyle,Lars P Ryder,Qing Lan,Emil Rehnberg,Anne Kricker,Stephen Leach,Sam Milliken,Lindsay M Morton,Richard K Severson,Mark P Purdue,Mads Melbye,Tongzhang Zheng,Ishak D Irwan,Claire M Vajdic,Susan L Slager,John J Spinelli,Edison T Liu,Patricia Hartge,Yawei Zhang,Christine F Skibola,Shelia Hoar Zahm ,Angela Brooks‐Wilson ,Hans Olov Adami ,Sophia Wang ,Bruce K Armstrong ,Lucía Conde ,Jianjun Li

doi:10.1371/journal.pgen.1001378

Abstract

Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.

Highlights

Non-Hodgkin lymphoma (NHL) represents a diverse group of B- and T-cell malignancies of lymphatic origin
298,168 single nucleotide polymorphisms (SNPs) were analyzed in Stage 1 (l = 1.028; l1000 = 1.055 [7]), in which we observed suggestive associations at 4q32.3, 6p21.32 and 10q25.3 (Table S3) with the strongest at rs2647012 (odds ratio (OR) = 0.58, PPCAadjusted = 1.59x1027) within the human leukocyte antigen (HLA) class II region on 6p21.32
In Stage 2, we carried out an in silico validation of the top 40 SNPs from Stage 1 (Table S5) in 213 follicular lymphoma (FL) cases and 750 controls from the San Francisco Bay Area, USA (Table 1), the study that reported an association at 6p21.32 [6]

Summary

Introduction

Non-Hodgkin lymphoma (NHL) represents a diverse group of B- and T-cell malignancies of lymphatic origin. We conducted a larger independent genome-wide scan of FL using 379 cases and 791 controls from the Scandinavian Lymphoma Etiology (SCALE) study of Sweden and Denmark, which was used in the validation of the previous GWAS [6]. This scan was followed by two stages of validation in European-ancestry cases of FL and other common B-cell NHL subtypes and controls from the US, Canada and Australia (Table 1, Table S1, Table S2, Figure 1)

Methods

Results

Discussion

Conclusion