Genetic Variations In Immune Regulatory Genes and The Risk For Diffuse Large B-Cell Lymphoma

There is growing evidence linking genetic variations of immune regulation genes to non-Hodgkin lymphoma (NHL) etiology. In a large consortial study, it has been recently reported that an increased risk for NHL, especially the major lymphoma subtype diffuse large B-cell lymphoma (DLBCL), with genetic variations in immune regulatory genes that mediate inflammation and autoimmunity. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 57 genetic variations of 7 candidate genes, and their relation to risk for DLBCL in Koreans.

The case-control series consisted of 192 de novo DLBCL treated at five hospitals throughout Korea from August 2001 through August 2009 and 192 individuals from the population with age and gender matched healthy volunteers. The DNA samples were genotyped using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (Sequenom, Inc., San Diego, CA). We genotyped 11 haplotype-tagging SNPs (htSNPs) of spleen tyrosine kinase (STK), 9 htSNPs of Fc fragment of IgG, low affinity IIa, receptor (FCGR2A), 3 htSNPs of Fc fragment of IgG, low affinity IIIa, receptor (FCGR3A), 15 htSNPs of interferon regulatory factor 4 (IRF4), 9 htSNPs of interleukin 7 receptor (IL7R), 7 htSNPs of interleukin 10 (IL10), and 3 htSNPs of tumor necrosis factor (TNF) genes. We used logistic regression to evaluate the association between genotypes and haplotypes with DLBCL. For DLBCL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the co-dominant model for each SNP. The haplotypes were reconstructed according to the genotyping data and the linkage disequilibrium status of these SNPs.

We did not find significant associations between the htSNPs of FCGR2A, FCGR3A, IRF4, IL7R, and TNF genes and the risk of DLBCL. However, the minor allele heterozygotes of the rs3021094 htSNP of IL10 gene (P-trend = 0.028) and the rs2991216 htSNP of the SYK gene (P-trend = 0.035) showed an increased risk of DLBCL. On 10-million permutation testing, the haplotype including rs3021094 variant allele of IL10 gene was significantly associated with an increased risk of DLBCL (P = 0.001), however, the haplotype including rs2991216 variant allele of STK gene was statistically insignificant (P = 0.055).

This study presents several novel aspects of the genetic susceptibility to develop DLBCL. Although this study did not show statistically significant association between STK htSNPs and risk for DLBCL on 10-millinon permutation testing, we demonstrated that genetic variants and haplotypes of IL10 gene showed the significantly increased risk for DLBCL. Larger studies that focus on the role of the STK and IL10 genes will support to confirm causal variants to develop diffuse large B-cell lymphoma.

No relevant conflicts of interest to declare.