B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS

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 non–Hodgkin lymphoma (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 ¼ 1,914), follicular lymphoma (n ¼ 1,733), and marginal zone lymphoma (MZL; n ¼ 407), using unconditional logistic regression. Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR ¼ 1.24; 95% confidence interval (CI), 1.08–1.43; T3 vs. T1: OR ¼ 1.81; 95% CI, 1.59–2.07; P-trend (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 ¼ 6.46 vs. no autoimmune condition and a T1 PRS, P_trend < 0.0001, P-interaction (P_interaction) ¼ 0.49]. Follicular lymphoma 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.