Background/Purpose: The determinants behind the increased risk of non-Hodgkin Lymphoma (NHL) in systemic lupus (SLE) are unclear. The most common type of NHL in SLE (as in the general population) is the Diffuse Large B-Cell lymphoma (DLBCL) subtype. Using data from a recent NHL genome-wide association study (GWAS), our objective was to determine if certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with the risk of DLBCL.

Methods: We focused on 28 SNPs associated with SLE in European Caucasians; all of these SNPs of which have been strongly associated with lupus risk, with a p value of 10-7 or stronger. Our hypothesis was that these SNPs would also be associated with DLBCL. GWAS data on European Caucasians from International Lymphoma Epidemiology Consortium (InterLymph) studies and participating cohort studies were based on a total of 3,857 DLBCL cases and 7,666 controls. For each SLE-related SNP, the odds ratios and 95% confidence intervals (CIs) were computed using a log-additive logistic regression model.  Results from three previously conducted DLBCL GWAS studies were pooled in a fixed-effect meta-analysis. With 28 multiple comparisons, an alpha of 0.05 would correspond to a Bonferroni-corrected p value of 0.0018.

Results: Among the 28 SLE-related SNPs investigated, two were clearly associated with risk of DLBCL when correcting for multiple comparisons. These two included the rs3024505 SNP on chromosome 1, a variant allele of IL10 (OR per risk allele =1.14, 95% CI 1.05-1.23, p value 0.0013), and the HLA SLE risk allele rs1270942 on chromosome 6 (OR per risk allele 1.20, 95% CI 1.08-1.33, p value 0.0007).  Of additional possible interest were the rs4810485 and rs2205960 SNPs.  The OR for the rs4810485 (CD40 gene) risk allele was 1.09 (5% CI 1.02, 1.16, p value 0.013). The rs2205960 SNP, encoding a cytokine of the tumor necrosis factor superfamily, TNFSF4 was associated with an OR per risk allele of 1.08, 95% CI 1.02-1.15, p value 0.044.

Discussion: In terms of a link between the SLE-related rs3024505 SNP and DLBCL, serum IL-10 levels have previously been suggested as a prognostic factor in NHL and IL-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein.  Existing data also suggest that some HLA polymorphisms influence risk of DLBCL, CD40 is a member of the tumour necrosis superfamily and it has a central role in regulating B-cell proliferation; CD40 is expressed on several B-cell neoplasms including DLBCL. Finally, tumor necrosis factor ligand superfamily involvement has been suggested in the pathology of malignant lymphomas.

Conclusion: These data suggest several plausible pathways linking DLBCL and SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lupus-related-snps-and-risk-of-diffuse-large-b-cell-non-hodgkin-lymphoma/