Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell NHL subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes.
Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL, n=1914), follicular lymphoma (FL, n=1733) and marginal zone lymphoma (MZL, n=407), using unconditional logistic regression.
Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk (T2 vs T1: odds ratio, OR=1.24, 95% confidence interval, CI=1.08-1.43; T3 vs T1: OR=1.81, 95% CI=1.59-2.07; P-trend<0.0001). DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell mediated autoimmune condition and a T3 PRS (OR=6.46 vs no autoimmune condition and a T1 PRS, P-trend<0.0001, p-interaction=0.49). FL and MZL risk demonstrated no evidence of joint associations or significant p-interaction.
Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions.
Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.
