Abstract
Profound disruption of immune function is an established risk factor for non-Hodgkin lymphoma. We report here a large-scale evaluation of common genetic variants in immune genes and their role in lymphoma. We genotyped 57 single nucleotide polymorphisms (SNP) from 36 candidate immune genes in 1,172 non-Hodgkin lymphoma cases and 982 population-based controls from a US multicenter study. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the association between individual SNP and haplotypes with non-Hodgkin lymphoma overall and five well-defined subtypes. A haplotype comprising SNPs in two proinflammatory cytokines, tumor necrosis factor-alpha and lymphotoxin-alpha (rs1800629, rs361525, rs1799724, rs909253, and rs2239704), increased non-Hodgkin lymphoma risk overall (OR, 1.31; 95% CI, 1.06-1.63; P = 0.01) and notably for diffuse large B cell (OR, 1.64; 95% CI, 1.23-2.19; P = 0.0007). A functional nonsynonymous SNP in the innate immune gene Fc gamma receptor 2A (FCGR2A; rs1801274) was also associated with non-Hodgkin lymphoma; AG and AA genotypes were associated with a 1.26-fold (95% CI, 1.01-1.56) and 1.41-fold (95% CI, 1.10-1.81) increased risk, respectively (P(trend) = 0.006). Among non-Hodgkin lymphoma subtypes, the association with FCGR2A was pronounced for follicular and small lymphocytic lymphomas. In conclusion, common variants in genes influencing proinflammatory and innate immune responses were associated with non-Hodgkin lymphoma risk overall and their effects could vary by subtype. Our results require replication but potentially provide important clues for investigating common genetic variants as susceptibility factors and in disease outcomes, treatment responses, and immunotherapy targets.
Highlights
Recent gene expression studies have provided novel insights into the pattern of gene dysregulation in non-Hodgkin lymphoma and established a molecular basis for subclassification of the two major pathologic subtypes, follicular and diffuse large B-cell lymphomas (DLBCL; refs. 1, 2)
We present all results of our investigation of common genetic variants for non-Hodgkin lymphoma overall and for each nonHodgkin lymphoma subtype (Supplementary Tables S1-S4)
In our analyses of all study participants (Whites and Blacks), polymorphisms for the proinflammatory cytokines, tumor necrosis factor (TNF; G-308A, rs1800629), and lymphotoxin-a (LTA; A252G, rs909253) were associated with increased risks for non-Hodgkin lymphoma and risks were elevated for DLBCL, as recently reported among Whites
Summary
Recent gene expression studies have provided novel insights into the pattern of gene dysregulation in non-Hodgkin lymphoma and established a molecular basis for subclassification of the two major pathologic subtypes, follicular and diffuse large B-cell lymphomas (DLBCL; refs. 1, 2). Recent gene expression studies further implicate host inflammatory responses [12] and the nuclear factor-nB (NF-nB) pathway, supporting the conceivable role for polymorphic alleles of key immunoregulatory genes and the risk for non-Hodgkin lymphoma [13]. The coordination of signals required to preserve the balance within this robust and pleiotropic network must be maintained in healthy individuals. Sustained perturbation of this balance, such as that caused by inherited gene mutations, can result in significant disease [e.g., Janus-activated kinase (JAK) 3 or interleukin (IL)-7 receptor A deficiency and severe combined immunodeficient disease (SCID); ref. Common genetic variants can alter the expression or function of key genes, disrupting the balance cytokines and cells on which various cytokines act [Thelper (Th) 1, Th2, and T-regulatory cells; ref. 15]; these common variants have been associated with outcomes in autoimmune disorders (e.g., lupus), cancer (e.g., gastric), and infectious diseases (e.g., Helicobacter pylori; refs. 16–18)
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