Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes

Susan L. Slager; Sara J. Achenbach; Yan W. Asmann; Nicola J. Camp; Kari G. Rabe; Lynn R. Goldin; Timothy G. Call; Tait D. Shanafelt; Neil E. Kay; Julie M. Cunningham; Alice H. Wang; J. Brice Weinberg; Aaron D. Norman; Brian K. Link; Jose F. Leis; Celine M. Vachon; Mark C. Lanasa; Neil E. Caporaso; Anne J. Novak; James R. Cerhan

doi:10.1158/1055-9965.EPI-12-1217

Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes

Susan L. Slager, Sara J. Achenbach, Yan W. Asmann, Nicola J. Camp, Kari G. Rabe, Lynn R. Goldin, Timothy G. Call, Tait D. Shanafelt, Neil E. Kay, Julie M. Cunningham, Alice H. Wang, J. Brice Weinberg, Aaron D. Norman, Brian K. Link, Jose F. Leis, Celine M. Vachon, Mark C. Lanasa, Neil E. Caporaso, Anne J. Novak, James R. Cerhan

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11 Scopus citations

Abstract

Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 30 untranslated region (UTR) of IRF8 (rs1044873, log additive OR 0.7, P 1.81 10 6). This SNP was not associated with the other NHL subtypes (all P > 0.05). Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. Impact: These data provide support that a functional variant within the 30UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.

Original language	English (US)
Pages (from-to)	461-466
Number of pages	6
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	22
Issue number	3
DOIs	https://doi.org/10.1158/1055-9965.EPI-12-1217
State	Published - Mar 2013

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General Medicine

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Slager, S. L., Achenbach, S. J., Asmann, Y. W., Camp, N. J., Rabe, K. G., Goldin, L. R., Call, T. G., Shanafelt, T. D., Kay, N. E., Cunningham, J. M., Wang, A. H., Weinberg, J. B., Norman, A. D., Link, B. K., Leis, J. F., Vachon, C. M., Lanasa, M. C., Caporaso, N. E., Novak, A. J., & Cerhan, J. R. (2013). Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes. Cancer Epidemiology Biomarkers and Prevention, 22(3), 461-466. https://doi.org/10.1158/1055-9965.EPI-12-1217

Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes. / Slager, Susan L.; Achenbach, Sara J.; Asmann, Yan W. et al.
In: Cancer Epidemiology Biomarkers and Prevention, Vol. 22, No. 3, 03.2013, p. 461-466.

Research output: Contribution to journal › Article › peer-review

Slager, SL, Achenbach, SJ, Asmann, YW, Camp, NJ, Rabe, KG, Goldin, LR, Call, TG, Shanafelt, TD, Kay, NE , Cunningham, JM, Wang, AH, Weinberg, JB, Norman, AD, Link, BK, Leis, JF, Vachon, CM, Lanasa, MC, Caporaso, NE, Novak, AJ & Cerhan, JR 2013, 'Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes', Cancer Epidemiology Biomarkers and Prevention, vol. 22, no. 3, pp. 461-466. https://doi.org/10.1158/1055-9965.EPI-12-1217

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title = "Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes",

abstract = "Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 30 untranslated region (UTR) of IRF8 (rs1044873, log additive OR 0.7, P 1.81 10 6). This SNP was not associated with the other NHL subtypes (all P > 0.05). Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. Impact: These data provide support that a functional variant within the 30UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.",

author = "Slager, {Susan L.} and Achenbach, {Sara J.} and Asmann, {Yan W.} and Camp, {Nicola J.} and Rabe, {Kari G.} and Goldin, {Lynn R.} and Call, {Timothy G.} and Shanafelt, {Tait D.} and Kay, {Neil E.} and Cunningham, {Julie M.} and Wang, {Alice H.} and Weinberg, {J. Brice} and Norman, {Aaron D.} and Link, {Brian K.} and Leis, {Jose F.} and Vachon, {Celine M.} and Lanasa, {Mark C.} and Caporaso, {Neil E.} and Novak, {Anne J.} and Cerhan, {James R.}",

year = "2013",

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doi = "10.1158/1055-9965.EPI-12-1217",

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T1 - Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes

AU - Slager, Susan L.

AU - Achenbach, Sara J.

AU - Asmann, Yan W.

AU - Camp, Nicola J.

AU - Rabe, Kari G.

AU - Goldin, Lynn R.

AU - Call, Timothy G.

AU - Shanafelt, Tait D.

AU - Kay, Neil E.

AU - Cunningham, Julie M.

AU - Wang, Alice H.

AU - Weinberg, J. Brice

AU - Norman, Aaron D.

AU - Link, Brian K.

AU - Leis, Jose F.

AU - Vachon, Celine M.

AU - Lanasa, Mark C.

AU - Caporaso, Neil E.

AU - Novak, Anne J.

AU - Cerhan, James R.

PY - 2013/3

Y1 - 2013/3

N2 - Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 30 untranslated region (UTR) of IRF8 (rs1044873, log additive OR 0.7, P 1.81 10 6). This SNP was not associated with the other NHL subtypes (all P > 0.05). Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. Impact: These data provide support that a functional variant within the 30UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.

AB - Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk. Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes. Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 30 untranslated region (UTR) of IRF8 (rs1044873, log additive OR 0.7, P 1.81 10 6). This SNP was not associated with the other NHL subtypes (all P > 0.05). Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology. Impact: These data provide support that a functional variant within the 30UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.

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Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes

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