Dataset Information

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

ABSTRACT: Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82x10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48x10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83x10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

SUBMITTER: Walsh KM

PROVIDER: S-EPMC4767445 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

Walsh Kyle M KM Codd Veryan V Rice Terri T Nelson Christopher P CP Smirnov Ivan V IV McCoy Lucie S LS Hansen Helen M HM Elhauge Edward E Ojha Juhi J Francis Stephen S SS Madsen Nils R NR Bracci Paige M PM Pico Alexander R AR Molinaro Annette M AM Tihan Tarik T Berger Mitchel S MS Chang Susan M SM Prados Michael D MD Jenkins Robert B RB Wiemels Joseph L JL Samani Nilesh J NJ Wiencke John K JK Wrensch Margaret R MR

Oncotarget 20151201 40

Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using ...[more]

PMID: 26646793

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Project description:BackgroundRelative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.ObjectiveWe performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.Design, setting, and participantsGenotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.Outcome measurements and statistical analysisOdds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.Results and limitationsLonger genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).ConclusionsOur investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.Patient summaryTelomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

Project description:Maintenance of telomere length has long been established to play a role in the biology of cancer and several studies suggest that it may be especially important in myeloid malignancies. To overcome potential bias in confounding and reverse causation of observational studies, we use both a polygenic risk score (PRS) and inverse-variance weighted (IVW) Mendelian randomization (MR) analyses to estimate the relationship between genetically predicted leukocyte telomere length (LTL) and acute myeloid leukemia (AML) risk in 498 cases and 2099 controls and myelodysplastic syndrome (MDS) risk in 610 cases and 1759 controls. Genetic instruments derived from four recent studies explaining 1.23-4.57% of telomere variability were considered. We used multivariable logistic regression to estimate odds ratios (OR, 95% confidence intervals [CI]) as the measure of association between individual single-nucleotide polymorphisms and myeloid malignancies. We observed a significant association between a PRS of longer predicted LTL and AML using three genetic instruments (OR = 4.03 per ~1200 base pair [bp] increase in LTL, 95% CI: 1.65, 9.85 using Codd et al. [Codd, V., Nelson, C.P., Albrecht, E., Mangino, M., Deelen, J., Buxton, J.L., Hottenga, J.J., Fischer, K., Esko, T., Surakka, I. et al. (2013) Identification of seven loci affecting mean telomere length and their association with disease. Nat. Genet., 45, 422-427 427e421-422.], OR = 3.48 per one-standard deviation increase in LTL, 95% CI: 1.74, 6.97 using Li et al. [Li, C., Stoma, S., Lotta, L.A., Warner, S., Albrecht, E., Allione, A., Arp, P.P., Broer, L., Buxton, J.L., Alves, A.D.S.C. et al. (2020) Genome-wide association analysis in humans links nucleotide metabolism to leukocyte telomere length. Am. J. Hum. Genet., 106, 389-404.] and OR = 2.59 per 1000 bp increase in LTL, 95% CI: 1.03, 6.52 using Taub et al. [Taub, M.A., Conomos, M.P., Keener, R., Iyer, K.R., Weinstock, J.S., Yanek, L.R., Lane, J., Miller-Fleming, T.W., Brody, J.A., Raffield, L.M. et al. (2022) Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed. Cell Genom., 2.] genetic instruments). MR analyses further indicated an association between LTL and AML risk (PIVW ≤ 0.049) but not MDS (all PIVW ≥ 0.076). Findings suggest variation in genes relevant to telomere function and maintenance may be important in the etiology of AML but not MDS.

Dataset Information

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

Publications

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk.

Similar Datasets

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