Common Variation at 6p21.31 (BAK1) Influences the Risk of Chronic Lymphocytic Leukemia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2012 Jun 16

PMID 22700719

Citations 49

Authors

Susan L Slager

Christine F Skibola

Maria Chiara Di Bernardo

Lucia Conde

Peter Broderick

Shannon K McDonnell

Lynn R Goldin

Naomi Croft

Amy Holroyd

Shelley Harris

Jacques Riby

Daniel J Serie

Neil E Kay

Timothy G Call

Paige M Bracci

Eran Halperin

Mark C Lanasa

Julie M Cunningham

Jose F Leis

Vicki A Morrison

Logan G Spector

Celine M Vachon

Tait D Shanafelt

Sara S Strom

Nicola J Camp

J Brice Weinberg

Estella Matutes

Neil E Caporaso

Rachel Wade

Martin J S Dyer

Claire Dearden

James R Cerhan

Daniel Catovsky

Richard S Houlston

Affiliations

Soon will be listed here.

Abstract

We performed a meta-analysis of 3 genome-wide association studies to identify additional common variants influencing chronic lymphocytic leukemia (CLL) risk. The discovery phase was composed of genome-wide association study data from 1121 cases and 3745 controls. Replication analysis was performed in 861 cases and 2033 controls. We identified a novel CLL risk locus at 6p21.33 (rs210142; intronic to the BAK1 gene, BCL2 antagonist killer 1; P = 9.47 × 10(-16)). A strong relationship between risk genotype and reduced BAK1 expression was shown in lymphoblastoid cell lines. This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development.

Citing Articles

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References

Higgins J, Thompson S . Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11):1539-58. DOI: 10.1002/sim.1186. View

Takeuchi O, Fisher J, Suh H, Harada H, Malynn B, Korsmeyer S . Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease. Proc Natl Acad Sci U S A. 2005; 102(32):11272-7. PMC: 1183578. DOI: 10.1073/pnas.0504783102. View

Conde L, Halperin E, Akers N, Brown K, Smedby K, Rothman N . Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat Genet. 2010; 42(8):661-4. PMC: 2913472. DOI: 10.1038/ng.626. View

Chittenden T, Harrington E, OConnor R, Flemington C, Lutz R, Evan G . Induction of apoptosis by the Bcl-2 homologue Bak. Nature. 1995; 374(6524):733-6. DOI: 10.1038/374733a0. View

Slager S, Rabe K, Achenbach S, Vachon C, Goldin L, Strom S . Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL. Blood. 2010; 117(6):1911-6. PMC: 3056639. DOI: 10.1182/blood-2010-09-308205. View

Di Bernardo M, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R . A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet. 2008; 40(10):1204-10. DOI: 10.1038/ng.219. View

Goldin L, Pfeiffer R, Li X, Hemminki K . Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. Blood. 2004; 104(6):1850-4. DOI: 10.1182/blood-2004-01-0341. View

Penegar S, Wood W, Lubbe S, Chandler I, Broderick P, Papaemmanuil E . National study of colorectal cancer genetics. Br J Cancer. 2007; 97(9):1305-9. PMC: 2360468. DOI: 10.1038/sj.bjc.6603997. View

Pharoah P, Antoniou A, Easton D, Ponder B . Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med. 2008; 358(26):2796-803. DOI: 10.1056/NEJMsa0708739. View

10.

Leu J, George D . Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria. Genes Dev. 2007; 21(23):3095-109. PMC: 2081976. DOI: 10.1101/gad.1567107. View

11.

Crowther-Swanepoel D, Di Bernardo M, Jamroziak K, Karabon L, Frydecka I, Deaglio S . Common genetic variation at 15q25.2 impacts on chronic lymphocytic leukaemia risk. Br J Haematol. 2011; 154(2):229-33. DOI: 10.1111/j.1365-2141.2011.08706.x. View

12.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

13.

Dai H, Meng X, Lee S, Schneider P, Kaufmann S . Context-dependent Bcl-2/Bak interactions regulate lymphoid cell apoptosis. J Biol Chem. 2009; 284(27):18311-22. PMC: 2709361. DOI: 10.1074/jbc.M109.004770. View

14.

Crowther-Swanepoel D, Broderick P, Di Bernardo M, Dobbins S, Torres M, Mansouri M . Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet. 2010; 42(2):132-6. PMC: 5321238. DOI: 10.1038/ng.510. View

15.

Weiss N . Geographical variation in the incidence of the leukemias and lymphomas. Natl Cancer Inst Monogr. 1979; (53):139-42. View

16.

Nica A, Parts L, Glass D, Nisbet J, Barrett A, Sekowska M . The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 2011; 7(2):e1002003. PMC: 3033383. DOI: 10.1371/journal.pgen.1002003. View

17.

Stevenson F, Caligaris-Cappio F . Chronic lymphocytic leukemia: revelations from the B-cell receptor. Blood. 2004; 103(12):4389-95. DOI: 10.1182/blood-2003-12-4312. View

18.

Hamblin T, Davis Z, Gardiner A, Oscier D, Stevenson F . Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999; 94(6):1848-54. View

19.

Eisen T, Matakidou A, Houlston R . Identification of low penetrance alleles for lung cancer: the GEnetic Lung CAncer Predisposition Study (GELCAPS). BMC Cancer. 2008; 8:244. PMC: 2535604. DOI: 10.1186/1471-2407-8-244. View