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 Asmann, Nicola J. Camp, Kari G. Rabe, Lynn R. Goldin, Timothy G. Call, Tait D. Shanafelt, Neil Elliot 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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)461-466
Number of pages6
JournalCancer Epidemiology Biomarkers and Prevention
Volume22
Issue number3
DOIs
StatePublished - Mar 2013

Fingerprint

Chromosome Mapping
B-Cell Chronic Lymphocytic Leukemia
Non-Hodgkin's Lymphoma
Genome-Wide Association Study
Single Nucleotide Polymorphism
Genes
Untranslated Regions
Meta-Analysis

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

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

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 22, No. 3, 03.2013, p. 461-466.

Research output: Contribution to journalArticle

Slager, Susan L ; Achenbach, Sara J. ; Asmann, Yan ; Camp, Nicola J. ; Rabe, Kari G. ; Goldin, Lynn R. ; Call, Timothy G. ; Shanafelt, Tait D. ; Kay, Neil Elliot ; Cunningham, Julie M ; Wang, Alice H. ; Weinberg, J. Brice ; Norman, Aaron D. ; Link, Brian K. ; Leis, Jose F. ; Vachon, Celine M ; Lanasa, Mark C. ; Caporaso, Neil E. ; Novak, Anne J ; Cerhan, James R. / Mapping of the irf8 gene identifies a 30UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-hodgkin lymphoma subtypes. In: Cancer Epidemiology Biomarkers and Prevention. 2013 ; Vol. 22, No. 3. pp. 461-466.
@article{833b2f09b6ef49968d7f38ff9920bb88,
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 Yan Asmann and Camp, {Nicola J.} and Rabe, {Kari G.} and Goldin, {Lynn R.} and Call, {Timothy G.} and Shanafelt, {Tait D.} and Kay, {Neil Elliot} 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",
month = "3",
doi = "10.1158/1055-9965.EPI-12-1217",
language = "English (US)",
volume = "22",
pages = "461--466",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "3",

}

TY - JOUR

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

AU - Camp, Nicola J.

AU - Rabe, Kari G.

AU - Goldin, Lynn R.

AU - Call, Timothy G.

AU - Shanafelt, Tait D.

AU - Kay, Neil Elliot

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.

UR - http://www.scopus.com/inward/record.url?scp=84876569737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876569737&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-12-1217

DO - 10.1158/1055-9965.EPI-12-1217

M3 - Article

VL - 22

SP - 461

EP - 466

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 3

ER -