Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes

Mitchell J Machiela, Qing Lan, Susan L Slager, Roel C H Vermeulen, Lauren R Teras, Nicola J Camp, James R Cerhan, John J Spinelli, Sophia S Wang, Alexandra Nieters, Joseph Vijai, Meredith Yeager, Zhaoming Wang, Hervé Ghesquières, James McKay, Lucia Conde, Paul I W de Bakker, David G Cox, Laurie Burdett, Alain Monnereau, Christopher R Flowers, Anneclaire J De Roos, Angela R Brooks-Wilson, Graham G Giles, Mads Melbye, Jian Gu, Rebecca D Jackson, Eleanor Kane, Mark P Purdue, Claire M Vajdic, Demetrius Albanes, Rachel S Kelly, Mariagrazia Zucca, Kimberly A Bertrand, Anne Zeleniuch-Jacquotte, Charles Lawrence, Amy Hutchinson, Degui Zhi, Thomas M Habermann, Brian K Link, Anne J Novak, Ahmet Dogan, Yan W Asmann, Mark Liebow, Carrie A Thompson, Stephen M Ansell, Thomas E Witzig, Hervé Tilly, Corinne Haioun, Thierry J Molina, Henrik Hjalgrim, Bengt Glimelius, Hans-Olov Adami, Göran Roos, Paige M Bracci, Jacques Riby, Martyn T Smith, Elizabeth A Holly, Wendy Cozen, Patricia Hartge, Lindsay M Morton, Richard K Severson, Lesley F Tinker, Kari E North, Nikolaus Becker, Yolanda Benavente, Paolo Boffetta, Paul Brennan, Lenka Foretova, Marc Maynadie, Anthony Staines, Tracy Lightfoot, Simon Crouch, Alex Smith, Eve Roman, W Ryan Diver, Kenneth Offit, Andrew Zelenetz, Robert J Klein, Danylo J Villano, Tongzhang Zheng, Yawei Zhang, Theodore R Holford, Jenny Turner, Melissa C Southey, Jacqueline Clavel, Jarmo Virtamo, Stephanie Weinstein, Elio Riboli, Paolo Vineis, Rudolph Kaaks, Heiner Boeing, Anne Tjønneland, Emanuele Angelucci, Simonetta Di Lollo, Marco Rais, Immaculata De Vivo, Edward Giovannucci, Peter Kraft, Jinyan Huang, Baoshan Ma, Yuanqing Ye, Brian C H Chiu, Liming Liang, Ju-Hyun Park, Charles C Chung, Dennis D Weisenburger, Joseph F Fraumeni, Gilles Salles, Martha Glenn, Lisa Cannon-Albright, Karen Curtin, Xifeng Wu, Karin E Smedby, Silvia de Sanjose, Christine F Skibola, Sonja I Berndt, Brenda M Birmann, Stephen J Chanock, Nathaniel Rothman

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.