Causal relationship between atrial fibrillation and leukocyte telomere length: A two sample, bidirectional Mendelian randomization study

Sha, Zimo; Hou, Tianzhichao; Zhou, Taojie; Yang, Dan; Bao, Yangyang; Jin, Qi; Ye, Jing; Lu, Yiming; Wu, Liqun

doi:10.3389/fcvm.2023.1093255

Cited by 6 publications

(4 citation statements)

References 51 publications

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“…Previous studies have reported that H3C4 is involved in the epigenetic regulation of gene expression [ 38 ], nucleosome assembly [ 39 ], and telomere organization [ 40 ]. Previous studies found that telomeres can maintain chromosomal stability and are associated with ageing and longevity [ 41 , 42 ]. Although tRF-Trp-CCA-014 did not affect cell senescence, it may regulate the expression level of H3C4 mRNA and protein to function in ageing; otherwise, the H3C4 isoforms of human, mouse, and fruit fly are conserved.…”

Section: Discussionmentioning

confidence: 99%

The Expression Pattern of tRNA-Derived Small RNAs in Adult Drosophila and the Function of tRF-Trp-CCA-014-H3C4 Network Analysis

Yang

Xiao

Yuán

et al. 2023

IJMS

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tRNA-derived small RNAs (tsRNAs) are derived from tRNA and include tRNA halves (tiRNAs) and tRNA fragments (tRFs). tsRNAs have been implicated in a variety of important biological functions, such as cell growth, transcriptional regulation, and apoptosis. Emerging evidence has shown that Ago1-guided and Ago2-guided tsRNAs are expressed at 3 and 30 days in Drosophila and that tRF biogenesis in fruit flies affects tRNA processing and tRNA methylation. However, a wide analysis of tsRNA patterns in different ages of Drosophila have not been reported via the small RNA sequencing method. In the present study, tsRNAs of young (7 days) and old (42 days) Drosophila were sequenced and their expression characteristics were analysed. Then, a specific tRF (named tRF-Trp-CCA-014) was determined and was found to be conserved in fruit flies, mice, and humans. The expression patterns of tRF-Trp-CCA-014 in different tissues and stages of fruit flies and mice, and mouse NIH/3T3 cells were detected. Furthermore, mouse embryonic fibroblast NIH/3T3 cells were used as a model to analyse the function and targets of tRF-Trp-CCA-014. The RNA-seq data of six groups (Mimics, Mimic NC, Inhibitors, Inhibitor NC, Aging (adriamycin), and Control (Normal)) in mouse NIH3T3 cells were analysed. The results showed that the number of tsRNAs at 42 days (417) was more than at 7 days (288); thus, it was enriched with age. tRFs-1 were the most enriched, followed by 5′-tRFs and 3′-tRFs. Twenty-one differentially expressed tsRNAs were identified between 7 days and 42 days. Then, the conserved tRF tRF-Trp-CCA-014 was identified and found to accumulate in aged fruit flies and aged mouse NIH3T3 cells. RNA-seq data showed that most differentially expressed genes were involved in the immune system, cancer: overview, and signal translation. Furthermore, tRF-Trp-CCA-014 was found to bind to the 3′UTR of H3C4 in a dual-luciferase reporter gene assay. tRF-Trp-CCA-014 and H3C4 were detected in the cytoplasm of aged NIH3T3 cells by RNA in situ hybridization. These results suggest that the H3C4 gene is the target of tRF-Trp-CCA-014. This study will advance the current understanding of tRF roles and their implication in Drosophila and mouse studies.

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Section: Discussionmentioning

confidence: 99%

The Expression Pattern of tRNA-Derived Small RNAs in Adult Drosophila and the Function of tRF-Trp-CCA-014-H3C4 Network Analysis

Yang

Xiao

Yuán

et al. 2023

IJMS

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“…The IVW approach was applied as the main MR model, which provides most accurate estimate under the assumption that the instrumental variables were all valid ( 39 ). In order to account for potential heterogeneity and horizontal pleiotropy, three additional approaches for MR analyses including MR-Egger regression, weighted median and weighted mode methods, were applied.…”

Section: Methodsmentioning

confidence: 99%

Causal factors of cardiovascular disease in end-stage renal disease with maintenance hemodialysis: a longitudinal and Mendelian randomization study

Tian,

Xu,

Wang

et al. 2024

Front. Cardiovasc. Med.

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BackgroundThe risk factors of cardiovascular disease (CVD) in end-stage renal disease (ESRD) with hemodialysis remain not fully understood. In this study, we developed and validated a clinical-longitudinal model for predicting CVD in patients with hemodialysis, and employed Mendelian randomization to evaluate the causal 6study included 468 hemodialysis patients, and biochemical parameters were evaluated every three months. A generalized linear mixed (GLM) predictive model was applied to longitudinal clinical data. Calibration curves and area under the receiver operating characteristic curves (AUCs) were used to evaluate the performance of the model. Kaplan-Meier curves were applied to verify the effect of selected risk factors on the probability of CVD. Genome-wide association study (GWAS) data for CVD (n = 218,792,101,866 cases), end-stage renal disease (ESRD, n = 16,405, 326 cases), diabetes (n = 202,046, 9,889 cases), creatinine (n = 7,810), and uric acid (UA, n = 109,029) were obtained from the large-open GWAS project. The inverse-variance weighted MR was used as the main analysis to estimate the causal associations, and several sensitivity analyses were performed to assess pleiotropy and exclude variants with potential pleiotropic effects.ResultsThe AUCs of the GLM model was 0.93 (with accuracy rates of 93.9% and 93.1% for the training set and validation set, sensitivity of 0.95 and 0.94, specificity of 0.87 and 0.86). The final clinical-longitudinal model consisted of 5 risk factors, including age, diabetes, ipth, creatinine, and UA. Furthermore, the predicted CVD response also allowed for significant (p < 0.05) discrimination between the Kaplan-Meier curves of each age, diabetes, ipth, and creatinine subclassification. MR analysis indicated that diabetes had a causal role in risk of CVD (β = 0.088, p < 0.0001) and ESRD (β = 0.26, p = 0.007). In turn, ESRD was found to have a causal role in risk of diabetes (β = 0.027, p = 0.013). Additionally, creatinine exhibited a causal role in the risk of ESRD (β = 4.42, p = 0.01).ConclusionsThe results showed that old age, diabetes, and low level of ipth, creatinine, and UA were important risk factors for CVD in hemodialysis patients, and diabetes played an important bridging role in the link between ESRD and CVD.

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“…This may suggest that accelerated telomere shortening is secondary to the onset of AF. This year, a Mendelian analysis was presented, indicating such a cause-and-effect relationship [117]. The consequences of AF incidence, however, make this novel inverse relationship difficult to explain.…”

Section: Telomeres and Afmentioning

confidence: 99%

DNA Methylation and Telomeres—Their Impact on the Occurrence of Atrial Fibrillation during Cardiac Aging

Grzeczka,

Graczyk,

Kordowitzki

2023

IJMS

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Atrial fibrillation (AF) is the most common arrhythmia in humans. AF is characterized by irregular and increased atrial muscle activation. This high-frequency activation obliterates the synchronous work of the atria and ventricles, reducing myocardial performance, which can lead to severe heart failure or stroke. The risk of developing atrial fibrillation depends largely on the patient’s history. Cardiovascular diseases are considered aging-related pathologies; therefore, deciphering the role of telomeres and DNA methylation (mDNA), two hallmarks of aging, is likely to contribute to a better understanding and prophylaxis of AF. In honor of Prof. Elizabeth Blackburn’s 75th birthday, we dedicate this review to the discovery of telomeres and her contribution to research on aging.

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Causal relationship between atrial fibrillation and leukocyte telomere length: A two sample, bidirectional Mendelian randomization study

Cited by 6 publications

References 51 publications

The Expression Pattern of tRNA-Derived Small RNAs in Adult Drosophila and the Function of tRF-Trp-CCA-014-H3C4 Network Analysis

The Expression Pattern of tRNA-Derived Small RNAs in Adult Drosophila and the Function of tRF-Trp-CCA-014-H3C4 Network Analysis

Causal factors of cardiovascular disease in end-stage renal disease with maintenance hemodialysis: a longitudinal and Mendelian randomization study

DNA Methylation and Telomeres—Their Impact on the Occurrence of Atrial Fibrillation during Cardiac Aging

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