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Multicenter Study
. 2016 Jul;25(7):1043-9.
doi: 10.1158/1055-9965.EPI-15-1329. Epub 2016 May 13.

Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia

Juhi Ojha  1 , Veryan Codd  2 , Christopher P Nelson  2 , Nilesh J Samani  2 , Ivan V Smirnov  3 , Nils R Madsen  4 , Helen M Hansen  4 , Adam J de Smith  5 , Paige M Bracci  5 , John K Wiencke  6 , Margaret R Wrensch  6 , Joseph L Wiemels  7 , Kyle M Walsh  8 ; ENGAGE Consortium Telomere Group
Affiliations
Multicenter Study

Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia

Juhi Ojha et al. Cancer Epidemiol Biomarkers Prev. 2016 Jul.

Abstract

Background: 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.

Methods: 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.

Conclusions: 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.

Impact: 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.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1
Figure 1. Forest plot showing the effect of alleles associated with longer leukocyte telomere length on CLL risk
Allelic odds ratios are plotted with 95% confidence intervals. The overall estimate is for the combined effect of all 8 SNPs, where the odds ratio relates to the change in CLL risk for one standard deviation increase in genotypically-estimated leukocyte telomere length. Odds ratios are based on combined data from 273 CLL patients and 5725 controls.
Figure 2
Figure 2. Boxplots of genotypically-estimated leukocyte telomere length (LTL) in CLL patients and controls from the Eastern Cooperative Oncology Group 2997 trial (ECOG) (N=179), Illumina iControls (N=3166), CLL patients from the Dana Farber Cancer Institute (DFCI) (N=94), Wellcome Trust controls (N=2559), and combined analyses (273 CLL patients, 5725 controls)
The vertical dotted line shows the average value in the pooled control sets (542bp). Crosses show samples means; center lines show sample medians. Box limits indicate the 25th and 75th percentiles; whiskers extend 1.5 times the interquartile range (IQR) from the 25th and 75th percentiles. Outliers are represented by dots. The notches in boxes are defined as ±1.58*IQR/sqrt(n) and give roughly 95% confidence intervals for sample medians. P-values are adjusted for the first five ancestry-informative principal components and, in the combined analysis, for genotyping platform.
Figure 3
Figure 3. Effect of increasing quintile of genotypically-estimated leukocyte telomere length on CLL risk in combined discovery and replication datasets
The odds ratios are relative to the median (third) quintile. Vertical bars correspond to 95% confidence intervals. Quintiles were defined among controls and ranges were: quintile one (115bp–432bp), quintile two (433bp–512bp), quintile three (513bp–582bp), quintile four (583bp–652bp), quintile five (653bp–1008bp). Odds ratios are based on combined data from 273 CLL patients and 5725 controls.
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