Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk

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Abstract

To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 × 10−9), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 × 10−10), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 × 10−7) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 × 10−7). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 × 10−6) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 × 10−6). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.

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Figure 1: Forest plots of effect size and direction for the SNPs associated with CLL risk.
Figure 2: Four newly discovered loci showing genome-wide level of evidence of association to CLL.
Figure 3: Cumulative impact of 10 variants on CLL risk.

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Acknowledgements

We thank L. Padyukov (Karolinska Institutet) and the EIRA group for providing control samples from the Swedish population for the Swedish replication study. We also acknowledge the work of S. Richards and R. Wade (CTSU, Oxford) in furbishing survival data from CLL-4. We are grateful to all clinicians for their involvement in patient ascertainment. Finally, we are grateful to all the patients and other individuals for their participation. This study makes use of data generated by the Wellcome Trust Case-Control Consortium 1 and 2. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Leukaemia Research Fund provided principal funding for the study (LRF05001 and 06002). Additional funding was provided by CLL Global Research Foundation, Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Arbib Fund. D.C.-S. was supported by the Institute of Cancer Research. Funding for the project was provided by the Wellcome Trust under awards 076113 and 085475. In the UK, National Health Service funding for the Royal Marsden Biomedical Research Centre is acknowledged. E.C. and A.E. acknowledge Fundación Genoma España and CICYT funding (SAF 08/3630) and the Red Ternática de Investigación Cooperativa en Cancer from the Insituto de Salud Carlos III. A.C. and M.T. acknowledge Xunta de Galicia funding for Spanish control population (PGIDIT 08CSA005208PR) and the support of the Spanish National Genotyping Center (USC Node).

Author information

R.S.H. designed the study, obtained funding, directed the study and oversaw analyses. R.S.H. drafted the manuscript, with help from D.C.-S., P.B., M.C.D.B. and S.E.D. M.C.D.B. performed statistical analyses. D.C.-S., M.C.D.B. and S.E.D. performed bioinformatics analyses. R.S.H. and D.C. established the parent study. R.S.H., D.C. and D.C.-S. developed patient recruitment and sample acquisition and performed sample collection of cases. For the GWA and UK replication series 1, D.C.-S. and P.B. supervised laboratory management and oversaw genotyping of cases. D.C.-S. conducted sequencing. J.M.A. and D.J.A. conceived of the Newcastle-based CLL study. J.M.A. established the study, supervised laboratory management and oversaw genotyping of cases and controls. N.J.S. performed sample management of cases and controls. A.G.H. developed the Newcastle Haematology Biobank, incorporating the Newcastle-based CLL study. T.M.-F., G.H.J., G.S., A.P., M.J.S.D., E. Matutes, C.D., R.J.H., A.R.P., D.O., D.J.A., J.R.B., G.P., C.P. and C.F. developed patient recruitment and sample acquisition and performed sample collection of cases. Coordination of the Spain replication series was conducted by E.C. and A.E. E.C. and A.E. provided CLL samples and compiled detailed phenotypic information from cases; A.C. provided controls and compiled detailed phenotypic information from controls. C.R.S. and E. Montserrat performed sample acquisition. Genotyping was performed by M.T. and A.C., and M.T. supervised laboratory management and quality control. For the Swedish case-control study, M.M. performed sample collection and prepared DNA. R.R. performed sample collection for all cases, while J.J., G.J. and K.E.S. performed sample collection of cases in the SCALE study. P.B. and D.C.-S. performed genotyping of cases and controls. All authors contributed to the final paper.

Correspondence to Richard S Houlston.

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