There are few established risk factors for non-Hodgkin lymphoma (NHL), a cancer of immune cells which has experienced one of the largest - and still unexplained - increases in incidence. Immune dysregulation has long been recognized as necessary for non-Hodgkin lymphoma etiology, but the nature of that dysregulation is still poorly understood. Opposite spectrums of immune dysregulation - immune suppression and immune activation - are implicated as NHL risk factors. Clinical and epidemiologic studies have established autoimmune disorders collectively as a risk factor for NHL. More recent consortial efforts among epidemiologic studies have further identified specific immune gene variations, including the tumor necrosis factor (TNF) and human leukocyte antigen (HLA) Class I and Class II genes, as NHL risk factors. We hypothesize that the chronic inflammation that results from autoimmune conditions, and the type of inflammation elicited, can be compounded by genetic susceptibility loci to increase NHL risk and influence which NHL subtype or cell lineage emerges. The overall objective of this application is to evaluate the contributions of genetic susceptibility loci to NHL risk jointly with chronic inflammation from autoimmune conditions on risk of NHL - and particularly B-cell NHLs and diffuse large B-cell lymphoma - among participating studies in the International Lymphoma Epidemiology (InterLymph) Consortium.
In Aim 1, we will determine the joint associations of confirmed susceptibility loci from the InterLymph Consortium genome-wide association study (GWAS) and autoimmune conditions on risk of NHL. We will conduct a case-control analysis of GWAS- confirmed loci, which will be available on 8,188 cases and 7,084 controls of European ancestry.
This aim will inform whether confirmed susceptibility loci act in concert with autoimmune conditions to alter NHL risk. No evidence of an interaction would suggest that alternative pathways might lead to the same disease entity, an important concept that would aid in therapeutic interventions aimed at the underlying disease biology.
In Aim 2, we will conduct a case-only approach to identify new gene variants associated with NHL, in the context of autoimmune conditions, among the 6,068 NHL cases with GWAS data. The rationale for this aim is based on the hypothesis that there are genetic susceptibility loci that exert their influence on chronic inflammation and NHL risk only in the presence of the appropriate environmental trigger. In summary, we propose to determine whether genetic susceptibility loci act in concert with or independent from immune conditions by conducting a biologically-driven and rigorous application of complementary statistical approaches for assessing gene- environment interaction in NHL.

Public Health Relevance

Successful completion of the largest study of NHL gene-environment interactions will yield important insights regarding our understanding of the fundamental biology that drives lymphomagenesis and yield potential targets for therapy and clues for prevention efforts. NARRATIVE: Immune dysregulation has long been recognized as necessary for non-Hodgkin lymphoma (NHL) etiology, but the nature of that dysregulation is still poorly understood. Autoimmune conditions result in chronic antigenic stimulation/inflammation and are a well-established risk factor for NHL;leveraging our understanding of their underlying biology offers significant potential for shedding light on key pathways that contribute to NHL risk in the general population. We therefore propose to evaluate the interaction between autoimmune conditions and gene variants on risk of NHL among participating case-control studies in the International Lymphoma Epidemiology (InterLymph) Consortium by employing two complementary statistical approaches: (i) a case- control approach to evaluate genome-wide association study (GWAS)-confirmed loci and (ii) an exploratory case-only approach of GWAS data to identify new susceptibility loci in the context of autoimmune conditions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Research Grants (R03)
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Special Emphasis Panel (ZCA1-SRLB-D (J1))
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Carrick, Danielle M
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City of Hope/Beckman Research Institute
United States
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