Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

Cancer Control Research and School of Population and Public Health University of British Columbia Vancouver BC Canada

Cancer Epidemiology Centre Cancer Council Victoria Melbourne VIC Australia Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health and

Cancer Epidemiology Research Programme Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain CIBER de Epidemiología y Salud Pública Barcelona Spain

Cancer Genomics Research Laboratory Division of Cancer Epidemiology and Genetics National Cancer Institute Gaithersburg MD USA

Center for Chronic Immunodeficiency University Medical Center Freiburg Freiburg Baden Württemberg Germany

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

Centre Heni Becquerel Université de Rouen Rouen France

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

Chronic Disease Prevention Unit National Institute for Health and Welfare Helsinki Finland

Danish Cancer Society Research Center Copenhagen Denmark

Department of Biomedical Science and

Department of Biostatistics University of Alabama at Birmingham Birmingham AL USA

Department of Biostatistics Yale School of Public Health New Haven CT USA

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

Department of Environmental and Occupational Health Drexel University School of Public Health Philadelphia PA USA Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA

Department of Environmental Health Sciences and

Department of Epidemiology

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

Department of Epidemiology and Carolina Center for Genome Sciences University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Epidemiology Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Department of Epidemiology Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA Department of Nutrition and

Department of Epidemiology College of Information Science and Technology Dalian Maritime University Dalian Liaoning Province China

Department of Epidemiology Department of Biostatistics Harvard School of Public Health Boston MA USA

Department of Epidemiology Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Epidemiology German Institute for Human Nutrition Potsdam Germany

Department of Epidemiology MD Anderson Cancer Center Houston TX USA

Department of Epidemiology MRC PHE Centre for Environment and Health School of Public Health and

Department of Epidemiology Research Division of Health Surveillance and Research Statens Serum Institut Copenhagen Denmark

Department of Epidemiology Research Division of Health Surveillance and Research Statens Serum Institut Copenhagen Denmark Department of Medicine Stanford University School of Medicine Stanford CA USA

Department of Epidemiology School of Public Health and Comprehensive Cancer Center and Division of Environmental Health Sciences University of California Berkeley School of Public Health Berkeley CA USA

Department of Family Medicine and Public Health Sciences Wayne State University Detroit MI USA

Department of Health Sciences Research

Department of Health Sciences University of York York UK

Department of Health Studies University of Chicago Chicago IL USA

Department of Hematology and Laboratoire de Biologie Moléculaire de la Cellule UMR 5239 Centre National de la Recherche Scientifique Pierre benite Cedex France

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Internal Medicine Carver College of Medicine The University of Iowa Iowa City IA USA

Department of Internal Medicine University of Utah School of Medicine Salt Lake City UT USA

Department of Medical Biosciences Umeå University Umeå Sweden

Department of Medicine and

Department of Medicine Solna Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Department of Pathology AP HP Necker Enfants malades Université Paris Descartes Sorbonne Paris Cité France

Department of Pathology City of Hope National Medical Center Duarte CA USA

Department of Population Health and Department of Environmental Medicine New York University School of Medicine New York NY USA Perlmutter Cancer Center NYU Langone Medical Center New York NY USA

Department of Preventive Medicine and Norris Comprehensive Cancer Center USC Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Public Health Clinical and Molecular Medicine University of Cagliari Monserrato Cagliari Italy

Department of Statistics Dongguk University Seoul Republic of Korea

Department of Surgery and Translational Medicine Section of Anatomo Pathology University of Florence Florence Italy

Departments of Laboratory Medicine and Pathology Memorial Sloan Kettering Cancer Center New York NY USA

Division of Biomedical Statistics and Informatics Department of Health Sciences Research Mayo Clinic Rochester MN USA

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Baden Württemberg Germany

Division of Cancer Etiology City of Hope Beckman Research Institute Duarte CA USA

Division of Endocrinology Diabetes and Metabolism The Ohio State University Columbus OH USA

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

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA

EA 4184 Registre des Hémopathies Malignes de Côte d'Or University of Burgundy and Dijon University Hospital Dijon France

Epidemiology of Childhood and Adolescent Cancers Group INSERM Center of Research in Epidemiology and Statistics Sorbonne Paris Cité Paris France Université Paris Descartes Paris France

Epidemiology of Childhood and Adolescent Cancers Group INSERM Center of Research in Epidemiology and Statistics Sorbonne Paris Cité Paris France Université Paris Descartes Paris France Registre des hémopathies malignes de la Gironde Institut Bergonié Bordeaux Cedex France

Epidemiology Research Program American Cancer Society Atlanta GA USA

Faculty of Medicine and Health Sciences Macquarie University Sydney NSW Australia Department of Histopathology Douglass Hanly Moir Pathology Sydney NSW Australia

Genetic Epidemiology Laboratory Department of Pathology University of Melbourne Melbourne VIC Australia

Genome Sciences Centre BC Cancer Agency Vancouver BC Canada Department of Biomedical Physiology and Kinesiology Simon Fraser University Burnaby BC Canada

Hematology Unit Ospedale Oncologico di Riferimento Regionale A Businco Cagliari Italy

Icahn Institute for Genomics and Multiscale Biology Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA

INSERM U1052 Cancer Research Center of Lyon Centre Léon Bérard Lyon France

Institute for Risk Assessment Sciences Utrecht University Utrecht The Netherlands Julius Center for Health Sciences and Primary Care and

International Agency for Research on Cancer Lyon France

Julius Center for Health Sciences and Primary Care and Department of Medical Genetics and of Epidemiology University Medical Center Utrecht Utrecht The Netherlands

Laboratoire de Biologie Moléculaire de la Cellule UMR 5239 Centre National de la Recherche Scientifique Pierre benite Cedex France Department of Hematology Hospices Civils de Lyon Pierre benite Cedex France Department of Hematology Université Lyon 1 Pierre benite Cedex France and

Lymphoid Malignancies Unit Henri Mondor Hospital and University Paris Est Créteil France

MRC PHE Centre for Environment and Health School of Public Health and Human Genetics Foundation Turin Italy

Ontario Health Study Toronto ON Canada

School of Nursing and Human Sciences Dublin City University Dublin Ireland

School of Public Health Imperial College London London UK

The Tisch Cancer Institute and

Westat Rockville MD USA

Winship Cancer Institute Emory University School of Medicine Atlanta GA USA

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Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma