scholarly journals Predicted Leukocyte Telomere Length and Risk of Myeloid Neoplasms

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1335-1335
Author(s):  
Jenny Poynter ◽  
Spencer Kelley ◽  
Marina Marcato ◽  
Erica Langer ◽  
Anthony J Hooten ◽  
...  
Keyword(s):  
Telomere Length ◽  
Myeloid Leukemia ◽  
Mendelian Randomization ◽  
Conflicts Of Interest ◽  
Case Control ◽  
Leukocyte Telomere Length ◽  
Case Control Studies ◽  
Myeloid Malignancy ◽  
Individual Snps ◽  
The Individual

Background Maintenance of telomere length has long been established to play a role in the biology of cancer, and several lines of evidence suggest that it may be especially important in myeloid malignancy. Measuring leukocyte telomere length (LTL) directly in case control studies is problematic because telomere length is likely to be influenced by the disease process. Recent studies have led to the identification of a robust genetic predictor of LTL, which we have used to compare differences in predicted telomere length in case control studies of myeloid leukemia and myelodysplastic syndromes (MDS) using Mendelian randomization (MR). MR is a method used to measure the association between a trait (e.g. telomere length) and an outcome (e.g. myeloid malignancy) that can't be measured directly by utilizing genetic variants known to be associated with the trait as instrumental variables. The use of genetic predictors of telomere length reduces the possibility that the association is explained by reverse causation and confounding likely to be relevant in case-control studies where telomere length is measured directly because genotypes in the general population should be randomly distributed. Additionally, predicted telomere length has the added advantage of representing telomere length over the lifetime of the individual while measuring LTL directly will represent only one time point in an individual's life. Methods Myeloid leukemia (AML and CML) and MDS cases were identified by rapid case ascertainment through the Minnesota Cancer Surveillance System (MCSS). Centralized pathology and cytogenetics reviews were conducted to confirm diagnosis and classify by subtypes. Controls were identified through the Minnesota State driver's license/identification card list. We used the Sequenom platform to genotype seven SNPs that were validated predictors of LTL in a recently published meta-analysis. We estimated associations between individual SNPs and myeloid malignancy using multivariable logistic regression. Mendelian randomization was used to evaluate the association between predicted LTL and risk of myeloid malignancy. Results We included 253 AML cases, 353 MDS cases, 145 CML cases, and 1,042 controls. We observed a significant association between longer predicted telomere length and AML in analyses adjusted for sex and age (OR 4.82 per additional kilobase of average telomere length, 95% CI 1.32-17.63). The individual SNP analyses suggest that the association is largely driven by rs10936599, located in TERC (OR 1.47 per allele, 95% CI 1.14-1.90; Figure). We did not observe statistically significant associations between predicted LTL and MDS or CML. Discussion In this analysis of predicted telomere length and myeloid malignancy, we identified a significant association between longer predicted leukocyte telomere length and AML. In contrast, no significant association was observed for MDS or CML although we did observe an elevated OR for longer predicted telomere length and MDS that did not reach statistical significance. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals Long Leukocyte Telomere Length Is Associated with Increased Risks of Soft Tissue Sarcoma: A Mendelian Randomization Study

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 594 ◽  
Author(s):  
Yifan Xu ◽  
Junfeng Xu ◽  
Haidee Chancoco ◽  
Maosheng Huang ◽  
Keila E. Torres ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Telomere Length ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Leukocyte Telomere Length ◽  
Nucleotide Polymorphisms ◽  
Individual Snps ◽  
Increased Risk ◽  
Weighted Genetic Risk Score

Background: Leukocyte telomere length (LTL) has been associated with the risks of several cancers in observational studies. Mendelian randomization (MR) studies, using genetic variants as instrumental variables, have also shown associations of genetically predicted LTL with cancer risks. In this study, we performed the first MR analysis on soft tissue sarcoma (STS) to investigate the causal relationship between LTL and the risk of STS. Methods: Genotypes from eleven LTL-associated single nucleotide polymorphisms (SNPs) in 821 STS cases and 851 cancer-free controls were aggregated into a weighted genetic risk score (GRS) to predict LTL. Multivariate logistic regression was used to assess the association of STS risk with individual SNPs and aggregated GRS. Results: Four SNPs displayed evidence for an individual association between long LTL-conferring allele and increased STS risk: rs7675998 (odds ratio (OR) = 1.21, 95% confidence interval (CI) = 1.02–1.43), rs9420907 (OR = 1.31, 95% CI = 1.08–1.59), rs8105767 (OR = 1.18, 95% CI = 1.02–1.37), and rs412658 (OR = 1.18, 95% CI = 1.02–1.36). Moreover, longer genetically predicted LTL, calculated as GRS, was strongly associated with an increased risk of STS (OR = 1.44, 95% CI = 1.18–1.75, p < 0.001), and there was a significant dose-response association (p for trend <0.001 in tertile and quartile analyses). The association of longer LTL with higher STS risk was more evident in women than in men. In stratified analyses by major STS subtypes, longer LTL was significantly associated with higher risks of leiomyosarcoma and gastrointestinal stromal tumors. Conclusions: Longer LTL is associated with increased risks of STS.

scholarly journals Association of leukocyte telomere length with chronic kidney disease in East Asians with type 2 diabetes: A Mendelian randomization study

2021 ◽  
Author(s):  
Resham L Gurung ◽  
Rajkumar Dorajoo ◽  
Yiamunaa M ◽  
Ling Wang ◽  
Sylvia Liu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Telomere Length ◽  
Mendelian Randomization ◽  
Random Effect ◽  
Leukocyte Telomere Length ◽  
Increased Risk ◽  
Genetically Determined

Abstract Background Chronic kidney disease (CKD) is common among type 2 diabetes (T2D) and increases the risk of kidney failure and cardiovascular diseases. Shorter leukocyte telomere length is associated with CKD in patients with T2D. We previously reported single nucleotide polymorphisms (SNPs) associated with leukocyte telomere length in Asian population. In this study, we elucidated the association of these SNPs with CKD in patients with T2D using Mendelian randomization (MR) approach. Methods The cross-sectional association of 16 leukocyte telomere length SNPs with CKD, defined as an estimated glomerular filtration rate of less than 60 ml/min/1.73m2 was assessed among 4,768 (1,628 cases, 3,140 controls) participants in the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes and Diabetic Nephropathy cohorts. MR analysis was performed using the random-effect inverse-variance weighted (IVW) method, the weighted median, MR-Egger and Radial MR adjusted for age and sex-stratified by cohorts and ethnicity (Chinese and Malays), then meta-analysed. Results Genetically determined shorter leukocyte telomere length was associated with increased risk of CKD in patients with T2D (meta-IVW adjusted odds ratio = 1.51 [95% confidence interval, 1.12 - 2.12; P = 0.007; Phet= 0.547]). Similar results were obtained following sensitivity analysis. MR-Egger analysis (intercept) suggested no evidence of horizontal pleiotropy (β  =  0.010, P = 0.751). Conclusions Our findings suggest that genetically determined leukocyte telomere length is associated with CKD in patients with T2D. Further studies are warranted to elucidate the causal role of telomere length in CKD progression.

scholarly journals Relative Leukocyte Telomere Length and Risk of Incident Ischemic Stroke in Men: A Prospective, Nested Case-Control Approach

2010 ◽  
Vol 13 (4) ◽  
pp. 411-414 ◽  
Author(s):  
Robert Y.L. Zee ◽  
Amy J. Castonguay ◽  
Nathaniel S. Barton ◽  
Paul M. Ridker
Keyword(s):  
Ischemic Stroke ◽  
Telomere Length ◽  
Case Control ◽  
Leukocyte Telomere Length ◽  
Control Approach ◽  
Nested Case Control

scholarly journals Leukocyte telomere length and amyotrophic lateral sclerosis: a Mendelian randomization study

2021 ◽  
Author(s):  
Kailin Xia ◽  
Linjing Zhang ◽  
Gan Zhang ◽  
Yajun Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Telomere Length ◽  
Causal Relationship ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Leukocyte Telomere Length ◽  
Weighted Median ◽  
Lateral Sclerosis

Abstract Background Observational studies have suggested that telomere length is associated with amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. We employed a two-sample Mendelian randomization (MR) approach to explore the causal relationship between leukocyte telomere length (LTL) and ALS based on the most cited and most recent and largest LTL genome-wide association studies (GWASs) that measured LTL with the Southern blot method (n = 9190) and ALS GWAS summary data (n = 80,610). We adopted the inverse variance weighted (IVW) method to examine the effect of LTL on ALS and used the weighted median method, simple median method, MR Egger method and MR PRESSO method to perform sensitivity analyses. Results We found that genetically determined longer LTL was inversely associated with the risk of ALS (OR = 0.846, 95% CI: 0.744–0.962, P = 0.011), which was mainly driven by rs940209 in the OBFC1 gene, suggesting a potential effect of OBFC1 on ALS. In sensitivity analyses, that was confirmed in MR Egger method (OR = 0.647,95% CI = 0.447–0.936, P = 0.050), and a similar trend was shown with the weighted median method (OR = 0.893, P = 0.201) and simple median method (OR = 0.935 P = 0.535). The MR Egger analyses did not suggest directional pleiotropy, showing an intercept of 0.025 (P = 0.168). Neither the influence of instrumental outliers nor heterogeneity was found. Conclusions Our results suggest that genetically predicted longer LTL has a causal relationship with a lower risk of ALS and underscore the importance of protecting against telomere loss in ALS.

scholarly journals Leukocyte telomere length in a population-based case–control study of ovarian cancer: a pilot study

2009 ◽  
Vol 21 (1) ◽  
pp. 77-82 ◽  
Author(s):  
Lisa Mirabello ◽  
Montserrat Garcia-Closas ◽  
Richard Cawthon ◽  
Jolanta Lissowska ◽  
Louise A. Brinton ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Pilot Study ◽  
Telomere Length ◽  
Case Control Study ◽  
Population Based ◽  
Case Control ◽  
Leukocyte Telomere Length ◽  
Control Study

scholarly journals Epidemiological and Mendelian Randomization Studies of Dihydrotestosterone and Estradiol and Leukocyte Telomere Length in Men

2016 ◽  
Vol 101 (3) ◽  
pp. 1299-1306 ◽  
Author(s):  
Bu B. Yeap ◽  
Matthew W. Knuiman ◽  
Mark L. Divitini ◽  
Jennie Hui ◽  
Gillian M. Arscott ◽  
...  
Keyword(s):  
Telomere Length ◽  
Mendelian Randomization ◽  
Leukocyte Telomere Length

Intensity Of Smoking Increases The Odds Of Acute Myeloid Leukemia In Adult Smokers

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2965-2965
Author(s):  
Sophia Fircanis ◽  
Priscilla Merriam ◽  
Naushaba Khan ◽  
Jorge J Castillo
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Response ◽  
Myeloid Leukemia ◽  
Meta Analysis ◽  
Case Control ◽  
Response Analysis ◽  
Case Control Studies ◽  
Male And Female ◽  
Never Smokers ◽  
Acute Myeloid

Abstract Introduction A number of risk factors for the development of acute myeloid leukemia (AML) have been previously described. The role of smoking in the development of AML has been postulated as a potential environmental risk factor. This association has been studied in previous observational reports; however, the dose-response relation between smoking and AML has not been evaluated. The primary objective of this meta-analysis is to evaluate the dose-relationship between smoking and the development of AML. Secondary objectives were to identify potential gender and/or geographical disparities. Methods A PubMed search from January 1, 1993 to December 31, 2012 was undertaken using the keywords: “(smoking OR tobacco OR cigarette) AND leukemia”. Prospective cohort and case-control studies reporting on the incidence of AML were included. Studies reporting on acute promyelocytic leukemia, acute leukemia or myeloid leukemia without specifying subtype and cross-sectional studies were excluded. Studies included in a previous meta-analysis by Brownson et al. (1993) were also excluded. The outcome of interest was the odds ratio (OR) with 95% confidence interval (CI) of developing AML in smokers compared to never smokers. Because the overall risk of AML in the general population is low, the relative risk mathematically approximates the OR, allowing the pooling of cohort and case-control studies (rare disease assumption). The random effects model (REM), which accounts for intra and inter-study heterogeneity, was used to estimate the combined outcome. Heterogeneity was also quantified by the I2statistic. Publication bias was assessed by the trim-and-fill analysis. Stratified analyses were performed in current smokers and ever smokers. Subset analyses were performed by sex, study design, geographical region, number of cigarettes smoked, number of years of smoking and cumulative smoking in pack-years. The quality of the studies was assessed by the Newcastle-Ottawa scale (NOS). Literature search, data gathering and quality assessment were performed independently by at least two of the investigators. All calculations and graphs were obtained using Comprehensive Meta-Analysis version 2.2.050 (Biostat, Englewood, NJ, USA). Results Our initial search yielded 573 articles, from which 16 case-control and 6 cohort studies were included in our final analysis; 10 studies were from Europe, 9 from North America and 3 from Asia. All the studies were considered of intermediate and high quality, based on the NOS score. Ever smokers had an OR of 1.26 (95% CI 1.15-1.38; p<0.01). The OR of AML in male and female ever smokers was 1.45 (95% CI 1.14-1.85; p<0.01) and 1.14 (95% CI 1.00-1.29; p=0.05), respectively. Current smokers had an OR of 1.42 (95% CI 1.24-1.62; p<0.01). Male and female current smokers had an OR 1.42 (95% CI 1.12-1.81; p<0.01) and 1.28 (95% CI 1.03-1.60; p=0.03), respectively. The odds of AML were increased in ever and current smokers regardless of the study design and the geographical region. Heterogeneity was minimal to moderate and publication bias analysis would have not changed our results. The dose-response analysis showed that smoking >20 cigarettes per day was associated with OR 1.76 (95% CI 1.41-2.18; p<0.01) while smoking <20 cigarettes with OR 1.38 (95% CI 1.23-1.55; p<0.01) of developing AML. Smoking >20 years showed OR of 1.35 (95% CI 1.16-1.57; p<0.01) but smoking <20 years was not associated with increased odds of AML (OR 1.04, 95% CI 0.90-1.20; p=0.56). Conclusions There is a 26% increase in the odds of developing of AML in those who have ever smoked compared to never smokers. In those who are current smokers the odds are increased by 42%. The odds of AML in male smokers appear somewhat higher than in female smokers but there does not appear to be a geographical disparity in the odds of AML based on smoking status. The dose-response analysis supports that the intensity of smoking might be a stronger driver of the odds of AML than the duration of smoking in adult individuals. Disclosures: No relevant conflicts of interest to declare.

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