title: Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia.
abstract: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Shorter mean telomere length in leukemic cells has been associated with more aggressive disease. Germline polymorphisms in telomere maintenance genes affect telomere length and may contribute to CLL susceptibility.
  
  
  
  We collected genome-wide data from two groups of patients with CLL (N = 273) and two control populations (N = 5,725). In ancestry-adjusted case-control comparisons, we analyzed eight SNPs in genes definitively associated with inter-individual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208, and RTEL1 RESULTS: Three of the eight LTL-associated SNPs were associated with CLL risk at P < 0.05, including those near: TERC [OR, 1.46; 95% confidence interval (CI), 1.15-1.86; P = 1.8 × 10(-3)], TERT (OR = 1.23; 95% CI, 1.02-1.48; P = 0.030), and OBFC1 (OR, 1.36; 95% CI, 1.08-1.71; P = 9.6 × 10(-3)). Using a weighted linear combination of the eight LTL-associated SNPs, we observed that CLL patients were predisposed to longer LTL than controls in both case-control sets (P = 9.4 × 10(-4) and 0.032, respectively). CLL risk increased monotonically with increasing quintiles of the weighted linear combination.
  
  
  
  Genetic variants in TERC, TERT, and OBFC1 are associated with both longer LTL and increased CLL risk. Because the human CST complex competes with shelterin for telomeric DNA, future work should explore the role of OBFC1 and other CST complex genes in leukemogenesis.
  
  
  
  A genetic predisposition to longer telomere length is associated with an increased risk of CLL, suggesting that the role of telomere length in CLL etiology may be distinct from its role in disease progression. Cancer Epidemiol Biomarkers Prev; 25(7); 1043-9. ©2016 AACR.
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Juhi
authors.initials: J
authors.lastname: Ojha
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Veryan
authors.initials: V
authors.lastname: Codd
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Smirnov
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Nils R
authors.initials: NR
authors.lastname: Madsen
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Hansen
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: de Smith
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors.forename: Paige M
authors.initials: PM
authors.lastname: Bracci
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.affiliation: Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California. Program in Neurologic Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Kyle.Walsh@ucsf.edu.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Walsh
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D059505:Telomere Homeostasis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor