Numerous epidemiological studies have shown a link between a personal history of autoimmune diseases and increased risk of specific lymphoma subtypes. Here, we compared the genetics of the NHL subtypes, FL, CLL/SLL and DLBCL, with the ADs, RA, T1D and CD using genome-wide association data to explore the hypothesis of a shared genetic background between lymphoma and ADs. Our analyses identified the presence of common genetic variants between NHL subtypes and ADs, suggesting a potential shared genetic mechanism. However, the co-localization of shared genetic variants was observed more often between FL and ADs than with the other NHL subtypes. Although several overlapping associated regions were found across the genome, only two that were located in the HLA Class I–III and II regions reached statistical significance. This non-random clustering in the HLA region supports the hypothesis that FL and autoimmune diseases might be influenced by a common set of immunoregulatory susceptibility genes.
Among the three ADs studied, CD exhibited the least genetic overlap with the three NHL subtypes studied. Although CD has been associated with risk of lymphoma (9
), it may be that the association is more a consequence of disease-related inflammatory processes or related to the immunosupressive therapies used to treat CD than to the presence of a shared genetic background.
We found several SNPs common to FL, RA and T1D, which were mainly located in intergenic or intronic regions. Among these, tag SNPs for HLA alleles were also identified, including tags for HLA-B*0702, HLA-DRB1*1301 and HLA-DQA1*0103, which showed protection for FL, RA and T1D. Whereas the use of tag SNPs to predict HLA allelotypes is acceptable for exploratory analyses and hypothesis generation, these findings will require validation and follow-up in HLA allelotype analyses. Further studies that include resequencing to exploit LD across all variants in the region are warranted to clarify and identify the causal variants and pathways that are unique and similar across these diseases.
Of particular interest was the observation that most of the SNPs in the HLA Class II region tended to exert the same effect on disease risk for FL and RA, but opposite effects for FL and T1D. Specifically, we found that the HLA-DRB1
*0101 allelotypes showed increased risk of FL and RA and a reduced risk of T1D. Similarly, other SNPs not listed as haplotype-tagging SNPs in (12
) had contrasting effects for FL and T1D. It could be that the alleles of these SNPs are tagging two different undetected allelotypes that are associated respectively with T1D and FL. It also might be that these alleles influence antigen presentation, and are important factors leading to different antigen-induced immune responses. Associations of opposite alleles to different autoimmune diseases have been observed in previous studies (13
) and it has been suggested that risk alleles for one disease may confer selective advantage for another disease or resistance to infection. Opposite effects of haplotypes in the HLA Class II region occur both across and within diseases, demonstrating the complexity of the HLA region. For example, there are several HLA Class II haplotypes that lie within the same region and yet have been shown to confer increased and decreased risk for FL (15
) and T1D (16
). Non-genetic factors associated with autoimmune disease such as chronic inflammation and treatment effects might also play a role in lymphomagenesis. Examples include the associations of Helicobacter pylori infection with gastric MALT lymphoma (17
) and Hepatitis C virus infection with B-cell NHL (18
). Further genotyping in additional cohorts will be necessary to validate these findings and to further explore the common genetic backgrounds between these two groups of diseases and their mechanisms of action.