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 = 1,914), follicular lymphoma (n = 1,733), 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: 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 (Ptrend) < 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, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. 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.

British Columbia Cancer Research Center Vancouver British Columbia Canada

Centre for Big Data Research in Health The University of New South Wales Sydney New South Wales Australia

Centre of Research in Epidemiology and Statistics UMR1153 INSERM Université de Paris Paris France

Channing Division of Network Medicine Department of Medicine Research Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts

Chao Family Comprehensive Cancer Center University of California Irvine Irvine California

Department of Biomedical Physiology and Kinesiology Faculty of Science Simon Fraser University Vancouver British Columbia Canada

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Cancer Prevention and Control at the National Cancer Center Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

Department of Environmental and Occupational Health Dornsife School of Public Health Drexel University Philadelphia Pennsylvania

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco California

Department of Epidemiology Fielding School of Public Health University of California Los Angeles Los Angeles California

Department of Epidemiology Research Statens Serum Institut Copenhagen Denmark

Department of Epidemiology School of Public Health Brown University Providence Rhode Island

Department of Health Sciences Research Mayo Clinic Rochester Minnesota

Department of Health Sciences University of York York United Kingdom

Department of Hematology The Hebrew University Hadassah Braun School of Public Health and Community Medicine Hadassah University Medical Center Jerusalem Israel

Department of Histopathology Douglass Hanly Moir Pathology Sydney New South Wales Australia

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Microbiology Immunology and Molecular Genetics David Geffen School of Medicine University of California Los Angeles Los Angeles California

Department of Obstetrics and Gynecology David Geffen School of Medicine University of California Los Angeles Los Angeles California

Department of Pathology City of Hope Duarte California

Department of Pathology Heersink School of Medicine The University of Alabama at Birmingham Birmingham Alabama

Department of Psychiatry and Biobehavioral Sciences David Geffen School of Medicine University of California Los Angeles Los Angeles California

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Rockville Maryland

Division of Clinical Epidemiology Department of Medicine Solna Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Division of Clinical Immunology and Rheumatology Department of Medicine Heersink School of Medicine The University of Alabama at Birmingham Birmingham Alabama

Division of Environmental Health Sciences School of Public Health University of California Berkeley Berkeley California

Division of Health Analytics Department of Computational and Quantitative Medicine Beckman Research Institute of the City of Hope Monrovia California

Faculty of Medicine Health and Human Sciences Macquarie University Sydney New South Wales Australia

O'Neal Comprehensive Cancer Center The University of Alabama at Birmingham Birmingham Alabama

Occupational Health Section Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy

Registre des Hémopathies Malignes de la Gironde Institut Bergonié University of Bordeaux Inserm Team EPICENE UMR 1219 Paris France

Registry of Hematological Malignancies of Cote d'Or INSERM U1231 Burgundy University and University Hospital Dijon France

Stony Brook Cancer Center Stony Brook University Stony Brook New York

Sydney School of Public Health The University of Sydney Sydney New South Wales Australia

The Biomedical Research Centre Network for Epidemiology and Public Health Madrid Spain

The Center for Chronic Immunodeficiency University Medical Center Freiburg Freiburg Germany

Unit of Infections and Cancer Epidemiology Public Health Cancer Prevention and Palliative Care Program Epibell IDIBELL Institut Català d' Oncologia IDIBELL Barcelona Spain

Winship Cancer Institute Emory University Atlanta Georgia

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