Dataset Information

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

ABSTRACT: Importance:The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. Objective:To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. Data Sources:Genomewide association studies (GWAS) published up to January 15, 2015. Study Selection:GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. Data Extraction and Synthesis:Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. Main Outcomes and Measures:Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. Results:Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420?081 cases (median cases, 2526 per disease) and 1?093?105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]). Conclusions and Relevance:It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

SUBMITTER: Telomeres Mendelian Randomization Collaboration

PROVIDER: S-EPMC5638008 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Haycock Philip C PC Burgess Stephen S Nounu Aayah A Zheng Jie J Okoli George N GN Bowden Jack J Wade Kaitlin Hazel KH Timpson Nicholas J NJ Evans David M DM Willeit Peter P Aviv Abraham A Gaunt Tom R TR Hemani Gibran G Mangino Massimo M Ellis Hayley Patricia HP Kurian Kathreena M KM Pooley Karen A KA Eeles Rosalind A RA Lee Jeffrey E JE Fang Shenying S Chen Wei V WV Law Matthew H MH Bowdler Lisa M LM Iles Mark M MM Yang Qiong Q Worrall Bradford B BB Markus Hugh Stephen HS Hung Rayjean J RJ Amos Chris I CI Spurdle Amanda B AB Thompson Deborah J DJ O'Mara Tracy A TA Wolpin Brian B Amundadottir Laufey L Stolzenberg-Solomon Rachael R Trichopoulou Antonia A Onland-Moret N Charlotte NC Lund Eiliv E Duell Eric J EJ Canzian Federico F Severi Gianluca G Overvad Kim K Gunter Marc J MJ Tumino Rosario R Svenson Ulrika U van Rij Andre A Baas Annette F AF Bown Matthew J MJ Samani Nilesh J NJ van t'Hof Femke N G FNG Tromp Gerard G Jones Gregory T GT Kuivaniemi Helena H Elmore James R JR Johansson Mattias M Mckay James J Scelo Ghislaine G Carreras-Torres Robert R Gaborieau Valerie V Brennan Paul P Bracci Paige M PM Neale Rachel E RE Olson Sara H SH Gallinger Steven S Li Donghui D Petersen Gloria M GM Risch Harvey A HA Klein Alison P AP Han Jiali J Abnet Christian C CC Freedman Neal D ND Taylor Philip R PR Maris John M JM Aben Katja K KK Kiemeney Lambertus A LA Vermeulen Sita H SH Wiencke John K JK Walsh Kyle M KM Wrensch Margaret M Rice Terri T Turnbull Clare C Litchfield Kevin K Paternoster Lavinia L Standl Marie M Abecasis Gonçalo R GR SanGiovanni John Paul JP Li Yong Y Mijatovic Vladan V Sapkota Yadav Y Low Siew-Kee SK Zondervan Krina T KT Montgomery Grant W GW Nyholt Dale R DR van Heel David A DA Hunt Karen K Arking Dan E DE Ashar Foram N FN Sotoodehnia Nona N Woo Daniel D Rosand Jonathan J Comeau Mary E ME Brown W Mark WM Silverman Edwin K EK Hokanson John E JE Cho Michael H MH Hui Jennie J Ferreira Manuel A MA Thompson Philip J PJ Morrison Alanna C AC Felix Janine F JF Smith Nicholas L NL Christiano Angela M AM Petukhova Lynn L Betz Regina C RC Fan Xing X Zhang Xuejun X Zhu Caihong C Langefeld Carl D CD Thompson Susan D SD Wang Feijie F Lin Xu X Schwartz David A DA Fingerlin Tasha T Rotter Jerome I JI Cotch Mary Frances MF Jensen Richard A RA Munz Matthias M Dommisch Henrik H Schaefer Arne S AS Han Fang F Ollila Hanna M HM Hillary Ryan P RP Albagha Omar O Ralston Stuart H SH Zeng Chenjie C Zheng Wei W Shu Xiao-Ou XO Reis Andre A Uebe Steffen S Hüffmeier Ulrike U Kawamura Yoshiya Y Otowa Takeshi T Sasaki Tsukasa T Hibberd Martin Lloyd ML Davila Sonia S Xie Gang G Siminovitch Katherine K Bei Jin-Xin JX Zeng Yi-Xin YX Försti Asta A Chen Bowang B Landi Stefano S Franke Andre A Fischer Annegret A Ellinghaus David D Flores Carlos C Noth Imre I Ma Shwu-Fan SF Foo Jia Nee JN Liu Jianjun J Kim Jong-Won JW Cox David G DG Delattre Olivier O Mirabeau Olivier O Skibola Christine F CF Tang Clara S CS Garcia-Barcelo Merce M Chang Kai-Ping KP Su Wen-Hui WH Chang Yu-Sun YS Martin Nicholas G NG Gordon Scott S Wade Tracey D TD Lee Chaeyoung C Kubo Michiaki M Cha Pei-Chieng PC Nakamura Yusuke Y Levy Daniel D Kimura Masayuki M Hwang Shih-Jen SJ Hunt Steven S Spector Tim T Soranzo Nicole N Manichaikul Ani W AW Barr R Graham RG Kahali Bratati B Speliotes Elizabeth E Yerges-Armstrong Laura M LM Cheng Ching-Yu CY Jonas Jost B JB Wong Tien Yin TY Fogh Isabella I Lin Kuang K Powell John F JF Rice Kenneth K Relton Caroline L CL Martin Richard M RM Davey Smith George G

JAMA oncology 20170501 5

<h4>Importance</h4>The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.<h4>Objective</h4>To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.<h4>Data sources</h4>Genomew ...[more]

PMID: 28241208

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Project description:BackgroundThe causal direction and magnitude of the associations between telomere length (TL) and cardiovascular diseases (CVDs) remain uncertain due to susceptibility of reverse causation and confounding. This study aimed to investigate the associations between TL and CVDs using Mendelian randomization (MR).Materials and methodsIn this two-sample MR study, we identified 154 independent TL-associated genetic variants from a genome-wide association study (GWAS) consisting of 472,174 individuals (aged 40-69) in the UK Biobank. Summary level data of CVDs were obtained from different GWASs datasets. Methods of inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), Mendelian Randomization robust adjusted profile score (MR-RAPS), maximum likelihood estimation, weighted mode, penalized weighted mode methods, and Mendelian randomization pleiotropy residual sum and outlier test (MR-PRESSO) were conducted to investigate the associations between TL and CVDs.ResultsOur findings indicated that longer TL was significantly associated with decreased risk of coronary atherosclerosis [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.75-0.95; P = 4.36E-03], myocardial infarction (OR, 0.72; 95% CI, 0.63-0.83; P = 2.31E-06), ischemic heart disease (OR, 0.87; 95% CI, 0.78-0.97; P = 1.01E-02), stroke (OR, 0.87; 95% CI, 0.79-0.95; P = 1.60E-03), but an increased risk of hypertension (OR, 1.12; 95% CI, 1.02-1.23; P = 2.00E-02). However, there was no significant association between TL and heart failure (OR, 0.94; 95% CI, 0.87-1.01; P = 1.10E-01), atrial fibrillation (OR, 1.01; 95% CI, 0.93-1.11; P = 7.50E-01), or cardiac death (OR, 0.95; 95% CI, 0.82-1.10; P = 4.80E-01). Both raw and outlier corrected estimates from MR-PRESSO were consistent with those of IVW results. The sensitivity analyses showed no evidence of pleiotropy (MR-Egger intercept, P > 0.05), while Cochran's Q test and MR-Egger suggested different degrees of heterogeneity.ConclusionOur MR study suggested that longer telomeres were associated with decreased risk of several CVDs, including coronary atherosclerosis, myocardial infarction, ischemic heart disease, and stroke, as well as an increased risk of hypertension. Future studies are still warranted to validate the results and investigate the mechanisms underlying these associations.

Project description:Background: Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue. Methods: This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses. Results: We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168–1.0524, p = 0.01] and 1.0127 (95% CI: 1.0046–1.0209, p = 6.36E-07), respectively. Conversely, TL shortening was validated to increase the odds of skin aging (OR = 0.96, 95% CI: 0.9332–0.9956, p = 0.03). Moreover, the MR-Egger, maximum likelihood, and inverse variance weighted (IVW) methods found significant heterogeneity among instrumental variable (IV) estimates (identified as MR-Egger skin aging Q = 76.72, p = 1.36E-04; melanoma Q = 97.10, p = 1.62E-07; NMSCsQ = 82.02, p = 1.90E-05). The leave-one-out analysis also showed that the SNP sensitivity was robust to each result. Conclusion: This study found that TL shortening may promote skin aging development and reduce the risk of cutaneous melanoma and NMSCs. The results provide a reference for future research on the causal relationship between skin aging and cancer in clinical practice.

Project description:BackgroundTelomere length has long been recognized as a valuable biomarker of aging and is inversely correlated with chronological age. Various lifestyle factors have been implicated in telomere shortening or preservation; however, the association between lifestyle factors and telomere length remains controversial. To address this issue, we conducted a Mendelian randomization (MR) analysis to investigate the potential causal associations between multiple lifestyle factors and telomere length.MethodsIndependent genetic variants strongly associated with lifestyle factors (tobacco smoking, sleep duration, insomnia, and physical activity) were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for telomere length was obtained from a GWAS comprising 472,174 European ancestries. Univariable and multivariable MR analyses were performed to assess the relationships.ResultsThe genetic liability to lifetime smoking was robustly associated with shorter telomere length (odd ratio [OR]: 0.882; 95% confidence interval [CI]: 0.847-0.918). Genetically predicted insomnia was also linked to shorter telomere length (OR: 0.972; 95% CI: 0.959-0.985), while no significant association was observed between sleep duration and telomere length. Furthermore, a suggestive association was found between moderate-to-vigorous physical activity and longer telomere length (OR: 1.680; 95% CI: 1.115-2.531). In multivariable MR analyses, adjusting for potential mediators such as body mass index, type 2 diabetes, alcohol consumption, and alcohol use disorder, the associations of lifetime smoking and insomnia with telomere length remained robust.ConclusionOur findings suggest that smoking and insomnia may contribute to telomere shortening, while physical activity may play a role in telomere length maintenance. These findings underscore the importance of managing positive risk factors and adopting a healthy lifestyle to promote telomere health.

Project description:BackgroundTelomere length is closely linked to the aging phenotype, where cellular aging results in the production of a cascade of cell factors and the senescence-associated secretory phenotype (SASP), leading to an inflammatory response. The presence of inflammation plays a crucial role in the formation of intracranial aneurysms. Nevertheless, the relationship between telomere length and intracranial aneurysms remains unclear. This study aims to explore the causal connection between telomere length and intracranial aneurysms through the utilization of Mendelian randomization (MR) analysis.MethodsData on telomere length were obtained from the genome-wide association studies conducted on the UK Biobank, comprising a total of 472,174 participants. Data on intracranial aneurysms were obtained from the summary dataset of the Global Genome-wide Association Study (GWAS) conducted by the International Stroke Genetics Consortium. The dataset consisted of 7,495 cases and 71,934 controls, all of European descent. Initially, the linkage disequilibrium score was used to investigate the connection between telomere length and intracranial aneurysms. Subsequently, a bidirectional MR was conducted using two-sample analysis to assess whether there is a causal connection between telomere length and intracranial aneurysm risk. The results were analyzed utilizing five MR methods, with the inverse variance weighted method serving as the main methodology. In addition, we did various analyses to evaluate the presence of heterogeneity, pleiotropy, and sensitivity in the study results. A reverse MR analysis was conducted to investigate potential reverse causal links.ResultsIn the forward MR analysis, it was observed that both the inverse variance-weighted and weighted median analyses implied a potential causal relationship between longer telomere length and a decreased incidence of intracranial aneurysms (IVW: OR = 0.66, 95% CI: 0.47-0.92, p = 1.49 × 10-2). There was no heterogeneity or horizontal pleiotropy. The findings were verified to be robust through the utilization of leave-one-out analysis. The use of reverse MR analysis did not establish a potential causal link between the occurrence of intracranial aneurysms and telomere length.ConclusionThere may exist a potential correlation between longer telomere length and a decreased likelihood of intracranial aneurysms within the European population. The present study offers novel insights into the correlation between telomere length and intracranial aneurysms. Additional research is required to clarify the underlying mechanisms and validate our discoveries in diverse populations.

Dataset Information

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

Publications

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

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