Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2014 Oct 2;95(4):462-71.
doi: 10.1016/j.ajhg.2014.09.004.

Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Christine F Skibola  1 , Sonja I Berndt  2 , Joseph Vijai  3 , Lucia Conde  4 , Zhaoming Wang  5 , Meredith Yeager  5 , Paul I W de Bakker  6 , Brenda M Birmann  7 , Claire M Vajdic  8 , Jia-Nee Foo  9 , Paige M Bracci  10 , Roel C H Vermeulen  11 , Susan L Slager  12 , Silvia de Sanjose  13 , Sophia S Wang  14 , Martha S Linet  2 , Gilles Salles  15 , Qing Lan  2 , Gianluca Severi  16 , Henrik Hjalgrim  17 , Tracy Lightfoot  18 , Mads Melbye  19 , Jian Gu  20 , Hervé Ghesquières  21 , Brian K Link  22 , Lindsay M Morton  2 , Elizabeth A Holly  10 , Alex Smith  18 , Lesley F Tinker  23 , Lauren R Teras  24 , Anne Kricker  25 , Nikolaus Becker  26 , Mark P Purdue  2 , John J Spinelli  27 , Yawei Zhang  28 , Graham G Giles  29 , Paolo Vineis  30 , Alain Monnereau  31 , Kimberly A Bertrand  32 , Demetrius Albanes  2 , Anne Zeleniuch-Jacquotte  33 , Attilio Gabbas  34 , Charles C Chung  2 , Laurie Burdett  5 , Amy Hutchinson  5 , Charles Lawrence  35 , Rebecca Montalvan  35 , Liming Liang  36 , Jinyan Huang  37 , Baoshan Ma  38 , Jianjun Liu  9 , Hans-Olov Adami  39 , Bengt Glimelius  40 , Yuanqing Ye  20 , Grzegorz S Nowakowski  12 , Ahmet Dogan  41 , Carrie A Thompson  42 , Thomas M Habermann  42 , Anne J Novak  42 , Mark Liebow  42 , Thomas E Witzig  42 , George J Weiner  22 , Maryjean Schenk  43 , Patricia Hartge  2 , Anneclaire J De Roos  44 , Wendy Cozen  45 , Degui Zhi  46 , Nicholas K Akers  47 , Jacques Riby  4 , Martyn T Smith  47 , Mortimer Lacher  3 , Danylo J Villano  3 , Ann Maria  3 , Eve Roman  18 , Eleanor Kane  18 , Rebecca D Jackson  48 , Kari E North  49 , W Ryan Diver  24 , Jenny Turner  50 , Bruce K Armstrong  25 , Yolanda Benavente  13 , Paolo Boffetta  51 , Paul Brennan  52 , Lenka Foretova  53 , Marc Maynadie  54 , Anthony Staines  55 , James McKay  56 , Angela R Brooks-Wilson  57 , Tongzhang Zheng  28 , Theodore R Holford  58 , Saioa Chamosa  59 , Rudolph Kaaks  26 , Rachel S Kelly  60 , Bodil Ohlsson  61 , Ruth C Travis  62 , Elisabete Weiderpass  63 , Jacqueline Clavel  64 , Edward Giovannucci  65 , Peter Kraft  36 , Jarmo Virtamo  66 , Patrizio Mazza  67 , Pierluigi Cocco  34 , Maria Grazia Ennas  68 , Brian C H Chiu  69 , Joseph F Fraumeni Jr  2 , Alexandra Nieters  70 , Kenneth Offit  3 , Xifeng Wu  20 , James R Cerhan  12 , Karin E Smedby  71 , Stephen J Chanock  2 , Nathaniel Rothman  2
Affiliations
Comparative Study

Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Christine F Skibola et al. Am J Hum Genet. .

Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Regional Plots of the FL-Associated Locus rs4938573 in 11q23.3 Figure shows the association results from the NCI FL GWAS and stages 1 and 2 combined (red diamond), recombination hotspots, and LD plots.
Figure 2
Figure 2
Regional Plots of the FL-Associated Locus rs4937362 in 11q24.3 Figure shows the association results from the NCI NHL GWAS and stages 1 and 2 combined (red diamond), recombination hotspots, and LD plots.
Figure 3
Figure 3
Regional Plots of the Associated Locus rs6444305 in 3q28 Figure shows the association results from the NCI FL GWAS and stages 1 and 2 combined (red diamond), recombination hotspots, and LD plots.
Figure 4
Figure 4
Regional Plots of the Associated Locus rs17749561 in 18q21.33 Figure shows the association results from the NCI FL GWAS and stages 1 and 2 combined (red diamond), recombination hotspots, and LD plots.
Figure 5
Figure 5
Regional Plots of the Associated Locus rs13254990 in 8q24.21 Figure shows the association results from the NCI FL GWAS and stages 1 and 2 combined (red diamond), recombination hotspots, and LD plots.
Figure 6
Figure 6
Sequential Conditioned Association Analysis in the HLA Region at 6p22.1-21.32: 29,400–33,400 kb Each gray diamond represents the p value from the meta-analysis of the four GWASs. Among all the AAs and HLA alleles tested, the top associated signal mapped to the AA DRβ1 at position 28 (top). After conditioning on DRβ1 28, rs17203612 in the HLA class II region was the marker with the highest association (second from top). Further analysis conditioning on both signals revealed rs3130437 in HLA class I as the most significant associated marker (second from bottom). No additional genome-wide significant signals were observed after controlling for the effects of DRβ1 28, rs17203612, and rs3130437 (bottom). Plots derived using genome assembly hg19.
See this image and copyright information in PMC

References

    1. Link B.K., Maurer M.J., Nowakowski G.S., Ansell S.M., Macon W.R., Syrbu S.I., Slager S.L., Thompson C.A., Inwards D.J., Johnston P.B. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J. Clin. Oncol. 2013;31:3272–3278. - PMC - PubMed
    1. Tan D., Horning S.J., Hoppe R.T., Levy R., Rosenberg S.A., Sigal B.M., Warnke R.A., Natkunam Y., Han S.S., Yuen A. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood. 2013;122:981–987. - PMC - PubMed
    1. Smedby K.E., Foo J.N., Skibola C.F., Darabi H., Conde L., Hjalgrim H., Kumar V., Chang E.T., Rothman N., Cerhan J.R. GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. PLoS Genet. 2011;7:e1001378. - PMC - PubMed
    1. Conde L., Halperin E., Akers N.K., Brown K.M., Smedby K.E., Rothman N., Nieters A., Slager S.L., Brooks-Wilson A., Agana L. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat. Genet. 2010;42:661–664. - PMC - PubMed
    1. Skibola C.F., Bracci P.M., Halperin E., Conde L., Craig D.W., Agana L., Iyadurai K., Becker N., Brooks-Wilson A., Curry J.D. Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat. Genet. 2009;41:873–875. - PMC - PubMed

Publication types