Data from Mapping of the <i>IRF8</i> Gene Identifies a 3′UTR Variant Associated with Risk of Chronic Lymphocytic Leukemia but not Other Common Non-Hodgkin Lymphoma Subtypes

Abstract

<div>Abstract<p><b>Background:</b> Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the <i>IRF8</i> 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 <i>IRF8</i> gene as a strong candidate for CLL risk.</p><p><b>Methods:</b> To refine the genetic association of CLL risk, we conducted Sanger sequencing of <i>IRF8</i> 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.</p><p><b>Results:</b> The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3′ untranslated region (UTR) of <i>IRF8</i> (rs1044873, log additive OR = 0.7, <i>P</i> = 1.81 × 10<sup>−6</sup>). This SNP was not associated with the other NHL subtypes (all <i>P</i> > 0.05).</p><p><b>Conclusions:</b> We provide evidence that rs1044873 in the <i>IRF8</i> 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 <i>IRF8</i> in CLL etiology.</p><p><b>Impact:</b> These data provide support that a functional variant within the 3′UTR of <i>IRF8</i> may be driving the GWAS signal seen on 16q24.1 for CLL risk. <i>Cancer Epidemiol Biomarkers Prev; 22(3); 461–6. ©2013 AACR</i>.</p></div>