To our knowledge, this is the first comprehensive analysis of interaction between blood transfusion, genetic polymorphisms in Th1/Th2 pathway genes, and the risk of NHL and its subtypes. Significant interactions were observed for IL10RA (rs9610) and TNF (rs1800629) for NHL overall and B-cell lymphoma. No interactions were observed for T-cell lymphoma; however, they were based on small numbers. Future larger studies with greater statistical power are needed to clarify the association with T-cell lymphoma.
are key genes to be linked to lymphomagenesis. Both genes encode immunoregulatory cytokines that are critical mediators of inflammation, apoptosis, and Th1/Th2 balance, and function as autocrine growth factors in lymphoid tumors [19
]. Studies of IL10
knockout mice have shown that each cytokine affects B-cell lymphomagenesis directly or indirectly [22
]. Prolonged red blood cell storage before transfusion has been reported can increase intracellular iron, which can exacerbate the systemic inflammatory response syndrome and lead to deleterious consequences [25
]. Blood transfusions also can suppress cellular immunity and transmit infectious agents and allogeneic cells [26
]. Therefore, it is possible that genetic variation in TNF
genes may modify the association between blood transfusion and risk of NHL.
Our study found that IL10RA
polymorphisms modified the association between blood transfusion and risk of NHL, particularly for B-cell lymphoma. IL10RA
gene encodes the interleukin 10 receptor-alpha chain of the IL10 receptor complex and plays a dominant role in mediating high affinity ligand binding and signal transduction [27
]. The IL10R
signaling causes transcriptional activation of several hundred genes, which play important roles in immunological diseases [29
]. IL10RA expression levels correlate with the strengths of the effects of IL10 on immune cells [30
]. Serum IL10 levels have been found to be higher in NHL patients [31
]. On the other hand, studies have shown that allogeneic nonleukofiltered red cell transfusion can significantly increase the production of IL10 [32
] and damaged autologous erythrocytes during blood transfusion can also elevate IL10 production [16
]. Although the underlying mechanism has yet to be established, effect modification observed in this study suggesting the IL10RA
pathway could play a role in the relationship between blood transfusion and risk of NHL. IL10RA
(rs9610) does not lead to amino acid substitution, but its importance to gene expression (translation and mRNA stability) cannot be ruled out.
The relationship between TNF
) polymorphism and NHL risk has been reported in several studies [33
], including this study [14
]. The TNF
) polymorphism has been found to be associated with higher constitutive and inducible expression of TNF-α and increased susceptibility to several infectious and inflammatory conditions [37
]. High levels of TNF-α promote activation of the transcription factor NF-κB, which has antiapoptotic effects on B cells [38
]. Inappropriate activation of NF-κB has also been linked to lymphomagenesis [39
] and to autoimmune diseases, which are known risk factors for NHL [3
]. Study also found that TNF
) polymorphism can induce immune suppression through an increased production of TNF-α [16
]. Recent evidence suggests that blood transfusion can increase serum levels of TNF-α [41
]. As such, the observed interaction between genetic variation of TNF
) and blood transfusion on the risk of NHL could be due to the change of TNF-α production.
Strengths and limitations should be considered in explaining the observed results. This study is a population-based case-control study with histologically confirmed incident NHL cases, which minimized potential disease misclassification. The study has a modest sample size, and therefore, the statistical power is limited particularly for NHL subtype analysis. As such, chance cannot be ruled out for some of the significant findings. Because of a number of SNPs being examined in the study, we adjusted for multiple comparisons using FDR approach. The study only included women, so the results may not be generalizable to men.
In summary, this is the first study to examine the effect modifications of common genetic variations in the Th1/Th2 pathways genes on the association between blood transfusion and risk of NHL. The observed significant interactions between IL10RA and TNF and blood transfusion on the risk of NHL need to be replicated in other study populations with greater statistical power.