Results of a study published in Genetic Epidemiology did not support a genetic association between specific autoimmune diseases and certain non-Hodgkin lymphoma (NHL) subtypes.

Previous research has established that there is an increased risk of Hodgkin lymphoma (HL) and NHL in patients with autoimmune diseases, such as multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren syndrome, systemic lupus erythematous (SLE), and celiac disease.

While no environmental risk factors have been identified as being associated with both autoimmune diseases and lymphomas, results of earlier meta-analyses of genome-wide association studies (GWAS) have suggested the possibility of genetic overlap between MS and HL, and SLE and diffuse large B-cell lymphoma (DLBCL).

This study was conducted to further explore potential genetic similarities between autoimmune diseases and lymphomas, and included 3 autoimmune diseases of interest (ie, MS, RA, and SLE), and 4 NHL subtypes (ie, DLBCL, follicular lymphoma, chronic lymphocytic leukemia [CLL], and marginal zone leukemia [MZL]).

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GWAS data sets were obtained from 4 previously conducted studies that listed “summary-level association results” for a large number of single-nucleotide polymorphisms (SNPs) of patients with MS, RA, SE, or the aforementioned NHL subtypes, as well for as healthy controls.

These 4 data sets were then “merged according to SNP name giving a final data set containing summary‐level results for a total of approximately 460,000 overlapping SNPs for MS and each NHL subtype; 600,000 overlapping SNPs for RA and each NHL subtype, and 600,000 SNPs for SLE and each NHL subtype.”

To evaluate whether there was SNP-level overlap between a specific autoimmune disease and a specific NHL subtype, SNPs independently associated with either disease were identified and grouped according to the significance of the association. A subset of the autoimmune-associated SNPs that reached an established level of significance was then evaluated for its association with a subset of NHL-subtype–associated SNPs that also met defined threshold criteria for significance.

The cumulative effect of SNPs, considering a large number of genes, in each autoimmune disease on each NHL subtype (ie, polygenic risk score) was determined for each individual by calculating the “weighted sum of the number of risk alleles at each SNP in the set, weighted by the log odds ratio of association for each SNP.” The ability of polygenic risk scores for patients with each autoimmune disease to separate patients with each NHL subtype from control patients, and vice versa, was then determined.

Meta-analyses were performed for each of the 12 autoimmune disease-NHL subtype combinations in the merged data set to assess all overlapping SNPs. In addition, the genetic overlap between autoimmune diseases and NHLs was also compared with the genetic overlap between autoimmune diseases and solid cancers.

Included in the study were data for 9772 patients with MS, 321 patients with RA, 7219 patients with SLE, 3617 patients with DLBCL, 2492 patients with CLL, 2686 patients with FL, 741 patients with MZL, and 46,436 controls.

Overall, the level of overlapping SNPs between autoimmune diseases and NHL subtypes was low.

Comparisons of polygenic risk scores of autoimmune diseases determined in NHL subtypes (and vice versa) were not able to significantly distinguish cases from controls. Furthermore, while considerable genetic overlap was observed between the NHL subtypes, a lower level of genetic overlap was observed between autoimmune diseases and NHL, although significantly more genetic overlap was demonstrated between autoimmune diseases and NHL compared with solid cancers (P =.0041).

Some of the limitations of this study, as identified by the study authors, included the absence of whole-exome coverage, as well as the relatively small sample size for some NHL subtypes.

“Altogether, within the limitations inherent in the available data our findings provide little evidence that shared genetic risk factors are a major explanation for the

increased risk of malignant B‐cell lymphomas in patients with autoimmune diseases, such as RA and SLE … other mechanisms, such as inflammation and chronic antigenic stimulation which increase B‐ and T‐cell receptor rearrangement and B‐cell somatic hypermutation, and/or [autoimmune disease] treatment with immunosuppressive or biologic therapy, seem likely to be more significant contributors to the long‐standing association between the two disease groups,” the study authors noted in conclusion.

Reference

Din L, Sheikh M, Kosaraju N, et al. Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes [published online August 13, 2019]. Genet Epidemiol. doi: 10.1002/gepi.22242