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.
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. SPECIFIC AIMS: 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. Today, NHL remains among the ten most common cancers worldwide in both men and women. Immune dysregulation has long been recognized as necessary for NHL etiology, with dysregulation at opposite spectrums - both immune suppression and immune activation - implicated in NHL etiology. Clinical and epidemiologic studies have well- established autoimmune disorders collectively as a NHL risk factor. Autoimmune conditions are characterized by autoreactivity and resultant chronic inflammation, an immune milieu conducive for lymphomagenesis. Recent research has identified tumor necrosis factor (TNF) and multiple human leukocyte antigen (HLA) gene variants, all located within the major histocompatibility complex on chromosome 6p21.3, to be associated with NHL. Confirmed NHL susceptibility loci now include the proinflammatory cytokine TNF promoter polymorphism (TNF -308A; rs1800629), rs10484561 (HLA Class II and part of an extended haplotype that includes HLA- DRB1*01:01), rs6457327 (HLA class I (HLA-C)), and rs2647012 (HLA Class II). Laboratory evidence that TNF G-308A directly elevates TNF? expression suggests that immune responses among individuals with TNF - 308A may have a predisposition for a proinflammatory immune response. Further, because different HLA alleles result in variations of the peptide-binding cleft, altered efficiency in antigen presentation may influence NHL etiology by affecting immune response to infections or tumor surveillance. We hypothesize that susceptibility loci associated with NHL and particularly B-cell NHLs such as diffuse large B-cell lymphoma (DLBCL), where the associations with autoimmune conditions are particularly pronounced, will act through an inflammatory pathway in concert with B-cell activating autoimmune conditions. 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. We recently conducted a proof-of-principle analysis among the International Lymphoma Epidemiology (InterLymph) Consortium studies that identified a statistically significant interaction between the TNF G-308A and autoimmune conditions, whereby B-cell NHL risks among those with one or more B-cell related autoimmune conditions and the variant TNF allele was the highest. 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 - and particularly B-cell NHLs and DLBCL - among participating InterLymph Consortium studies where autoimmune variables have been harmonized and where a genome-wide association study (GWAS) was recently completed. The 8,188 cases and 7,084 controls of European ancestry with genetic and autoimmune data from the InterLymph Consortium make it well-powered and efficient for evaluating joint associations between autoimmune conditions and gene variants. We propose to conduct a biologically-driven and rigorous analytic study comprising two complementary statistical approaches for assessing gene-environment interaction. Specific Aims 1) 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 evaluate multiplicative interaction of confirmed susceptibility loci using a case-control design (8,188 cases and 7,084 controls of European ancestry). This aim will inform whether any of the identified loci act in concert with autoimmune conditions to alter NHL risk. For the growing number of SNPs implicated in the 6p21.3 region, we will leverage on-going InterLymph GWAS efforts to impute HLA alleles, permitting us to directly evaluate whether Class II/antigen presentation or Class I/cytotoxic activity interacts with autoimmune conditions to alter NHL risk. 2) Conduct a case-only approach to identify new gene variants associated with NHL, in the context of autoimmune conditions. In this exploratory analysis, we will evaluate multiplicative interaction using a case-only design using GWAS data available on 6,068 NHL cases. We hypothesize 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. The case-only approach is recognized as a powerful and efficient way for evaluating gene-environment interactions under a multiplicative model. We thus aim to identify gene variants that were not previously identified in the initial GWAS scan, but ar identified in the context of specific autoimmune mechanisms to alter NHL risk. Successful completion of our study 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.
| Wang, Sophia S; Carrington, Mary; Berndt, Sonja I et al. (2018) HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes. Cancer Res 78:4086-4096 |
| Wang, Sophia S; Vajdic, Claire M; Linet, Martha S et al. (2015) Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci. Am J Epidemiol 181:406-21 |
