Associations between Longer Leukocyte Telomere Length and Increased Lung Cancer Risk among Never Smokers in Urban China.

BACKGROUND: The complex relationship between measured leukocyte telomere length (LTL), genetically predicted LTL (gTL), and carcinogenesis is exemplified by lung cancer. We previously reported associations between longer pre-diagnostic LTL, gTL, and increased lung cancer risk among European and East Asian populations. However, we had limited statistical power to examine the associations among never smokers by gender and histology. METHODS: To investigate further, we conducted nested case-control analyses on an expanded sample of never smokers from the prospective Shanghai Women's Health Studies (798 cases and 792 controls) and Shanghai Men's Health Studies (161 cases and 162 controls). We broke the case-control matching and used multivariable unconditional logistic regression models to estimate the ORs and 95% confidence intervals (CI) of incident lung cancer and adenocarcinoma (LUAD), in relation to LTL measured using quantitative PCR and gTL determined using a polygenic score. In addition, we conducted Mendelian randomization (MR) using MR-PRESSO. RESULTS: We found striking dose-response relationships between longer LTL and gTL, and increased lung cancer risk among never-smoking women (P trendLTL = 4×10-6; P trendgTL = 3×10-4). Similarly, among never-smoking men, longer measured LTL was associated with over triple the risk compared with those with the shortest (OR, 3.48; 95% CI, 1.85-6.57). The overall results were similar for LUAD among women and men. MR analyses supported causal associations with LUAD among women (OR1 SD gTL, 1.19; 95% CI, 1.03-1.37; P = 0.03). CONCLUSIONS: Longer pre-diagnostic LTL is associated with increased lung cancer risk among never smokers. IMPACT: Our findings firmly support the role of longer telomeres in lung carcinogenesis.

Mitochondrial DNA Fragmentation and Risk of Non-Hodgkin Lymphoma.

Importance: Research suggests that increased mitochondrial DNA copy number (mtDNAcn) is associated with increased risk of non-Hodgkin lymphoma (NHL); however, no studies to date have evaluated whether the mitochondrial DNA fraction with breaks (mtDNAfb) is associated with risk of NHL. Objective: To evaluate the association of mtDNAfb with NHL risk. Design, Setting, and Participants: This nested case-control study, which used prospectively collected samples as part of baseline enrollment (from 1985 through 1988) of 29 133 men who smoked for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study conducted in southwest Finland, included 107 incident NHL cases and 107 controls (matched on date of birth ±5 years). Analyses were conducted from January to September 2022. Exposure: High-throughput real-time polymerase chain reaction assays quantifying mtDNAfb. Main Outcomes and Measures: Incident NHL cases were identified in the ATBC Study through April 30, 2002, using the Finnish Cancer Registry and the Register of Causes of Death. The mtDNAfb was quantified and categorized based on the median, tertile, and quartile distributions among controls. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression models to assess the associations between categorized mtDNAfb and future risk of NHL, controlling for age, body mass index, number of cigarettes smoked per day, number of pack-years, and mtDNAcn. Results: A total of 29 133 men (median [IQR] age, 57.2 [52.6-62.5] years) participated in ATBC Study. Higher mtDNAfb was associated with an increased risk of NHL (median OR, 2.89; 95% CI, 1.40-5.93) in a dose-dependent manner (quartile 2 vs 1 OR, 1.24; 95% CI, 0.43-3.40; quartile 3 vs 1 OR, 3.58; 95% CI, 1.39-9.24; quartile 4 vs 1 OR, 3.42; 95% CI, 1.30- 8.99; P = .004 for trend). Conclusions and Relevance: This study's findings suggest that increased mtDNAfb is associated with an increased future risk of NHL. Additional studies are needed to confirm these findings, particularly among women and nonsmokers.

Household air pollution and epigenetic aging in Xuanwei, China.

BACKGROUND: Household air pollution (HAP) from indoor combustion of solid fuel is a global health burden linked to lung cancer. In Xuanwei, China, lung cancer rate for nonsmoking women is among the highest in the world and largely attributed to high levels of polycyclic aromatic hydrocarbons (PAHs) that are produced from combustion of smoky (bituminous) coal used for cooking and heating. Epigenetic age acceleration (EAA), a DNA methylation-based biomarker of aging, has been shown to be highly correlated with biological processes underlying the susceptibility of age-related diseases. We aim to assess the association between HAP exposure and EAA. METHODS: We analyzed data from 106 never-smoking women from Xuanwei, China. Information on fuel type was collected using a questionnaire, and validated exposure models were used to predict levels of 43 HAP constituents. Exposure clusters were identified using hierarchical clustering. EAA was derived for five epigenetic clocks defined as the residuals resulting from regressing each clock on chronological age. We used generalized estimating equations to test associations between exposure clusters derived from predicted levels of HAP exposure, ambient 5-methylchrysene (5-MC), a PAH previously found to be associated with risk of lung cancer, and EAA, while accounting for repeated-measurements and confounders. RESULTS: We observed an increase in GrimAge EAA for clusters with 31 and 33 PAHs reflecting current (ß = 0.77 y per standard deviation (SD) increase, 95 % CI:0.36,1.19) and childhood (ß = 0.92 y per SD, 95 % CI:0.40,1.45) exposure, respectively. 5-MC (ng/m3-year) was found to be associated with GrimAge EAA for current (ß = 0.15 y, 95 % CI:0.05,0.25) and childhood (ß = 0.30 y, 95 % CI:0.13,0.47) exposure. CONCLUSIONS: Our findings suggest that exposure to PAHs from indoor smoky coal combustion, particularly 5-MC, is associated with GrimAge EAA, a biomarker of mortality.

Exposure to smoky coal combustion emissions and leukocyte Alu retroelement copy number.

Household air pollution (HAP) from indoor combustion of solid fuel is a global health burden that has been linked to multiple diseases including lung cancer. In Xuanwei, China, lung cancer rate for non-smoking women is among the highest in the world and largely attributed to high levels of polycyclic aromatic hydrocarbons (PAHs) that are produced from combustion of smoky (bituminous) coal. Alu retroelements, repetitive mobile DNA sequences that can somatically multiply and promote genomic instability have been associated with risk of lung cancer and diesel engine exhaust exposure. We conducted analyses for 160 non-smoking women in an exposure assessment study in Xuanwei, China with a repeat sample from 49 subjects. Quantitative PCR was used to measure Alu repeat copy number relative to albumin gene copy number (Alu/ALB ratio). Associations between clusters derived from predicted levels of 43 HAP constituents, 5-methylchrysene (5-MC), a PAH previously associated with lung cancer in Xuanwei and was selected a priori for analysis, and Alu repeats were analyzed using generalized estimating equations. A cluster of 31 PAHs reflecting current exposure was associated with increased Alu copy number (ß:0.03 per standard deviation change; 95% confidence interval (CI):0.01,0.04; P-value = 2E-04). One compound within this cluster, 5-MC, was also associated with increased Alu copy number (P-value = 0.02). Our findings suggest that exposure to PAHs due to indoor smoky coal combustion may contribute to genomic instability. Additionally, our study provides further support for 5-MC as a prominent carcinogenic component of smoky coal emissions. Further studies are needed to replicate our findings.

Association of Telomere Length with Colorectal Cancer Risk and Prognosis: A Systematic Review and Meta-Analysis.

(1) Background: Colorectal cancer risk and survival have previously been associated with telomere length in peripheral blood leukocytes and tumor tissue. A systematic review and meta-analysis of the literature was conducted. The PubMed, Embase, and Web of Science databases were searched through March 2022. (2) Methods: Relevant studies were identified through database searching following PRISMA guidelines. Risk estimates were extracted from identified studies; meta-analyses were conducted using random effects models. (3) Results: Fourteen studies were identified (eight on risk; six on survival) through systematic review. While no association was observed between circulating leukocyte telomere length and the risk of colorectal cancer [overall OR (95% CI) = 1.01 (0.82-1.24)], a worse survival for those with shorter telomeres in leukocytes and longer telomeres in tumor tissues was observed [Quartile1/Quartile2-4 overall HR (95% CI) = 1.41 (0.26-7.59) and 0.82 (0.69-0.98), respectively]. (4) Conclusions: Although there was no association with colorectal cancer risk, a poorer survival was observed among those with shorter leukocyte telomere length. Future larger studies evaluating a potentially non-linear relationship between telomeres and colorectal cancer are needed.

Association of circulating leukocyte telomere length with survival in patients with colorectal cancer.

INTRODUCTION: Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. We investigated the association between circulating telomere length and overall and disease-free survival in a sub-cohort of patients with colorectal cancer. METHODS: Baseline genomic DNA from blood leukocytes was extracted from N = 92 newly diagnosed stage I-IV patients with colorectal cancer enrolled at the ColoCare Study site in Heidelberg, Germany. Detailed information on clinicodemographic (including age) and lifestyle risk factors, and clinical outcomes (including recurrence and survival) was collected. Telomere length was measured in DNA using multiplex quantitative polymerase chain reaction. Kaplan Meier survival curves were generated comparing shorter to longer telomere lengths with log-rank testing. RESULTS: The mean T/S ratio for study patients was 0.5 (range: 0.3-0.9). Shorter telomeres were associated with older age at baseline. Patients with shorter telomeres experienced a worse overall and disease-free survival, although this association did not reach statistical significance. Kaplan-Meier survival curves for those with circulating telomere length below vs. above the median showed poorer overall (log-rank p = 0.31) and disease-free survival (long-rank p = 0.23). CONCLUSIONS: Our results suggest that individuals with shorter telomeres, as seen with aging, may experience a worse overall and disease-free survival after colorectal cancer diagnosis. Larger sample sizes with longer follow-up are needed to further evaluate telomere length as a prognostic biomarker in colorectal cancer progression.

Elevated Alu retroelement copy number among workers exposed to diesel engine exhaust.

BACKGROUND: Millions of workers worldwide are exposed to diesel engine exhaust (DEE), a known genotoxic carcinogen. Alu retroelements are repetitive DNA sequences that can multiply and compromise genomic stability. There is some evidence linking altered Alu repeats to cancer and elevated mortality risks. However, whether Alu repeats are influenced by environmental pollutants is unexplored. In an occupational setting with high DEE exposure levels, we investigated associations with Alu repeat copy number. METHODS: A cross-sectional study of 54 male DEE-exposed workers from an engine testing facility and a comparison group of 55 male unexposed controls was conducted in China. Personal air samples were assessed for elemental carbon, a DEE surrogate, using NIOSH Method 5040. Quantitative PCR (qPCR) was used to measure Alu repeat copy number relative to albumin (Alb) single-gene copy number in leucocyte DNA. The unitless Alu/Alb ratio reflects the average quantity of Alu repeats per cell. Linear regression models adjusted for age and smoking status were used to estimate relations between DEE-exposed workers versus unexposed controls, DEE tertiles (6.1-39.0, 39.1-54.5 and 54.6-107.7 µg/m3) and Alu/Alb ratio. RESULTS: DEE-exposed workers had a higher average Alu/Alb ratio than the unexposed controls (p=0.03). Further, we found a positive exposure-response relationship (p=0.02). The Alu/Alb ratio was highest among workers exposed to the top tertile of DEE versus the unexposed controls (1.12±0.08 SD vs 1.06±0.07 SD, p=0.01). CONCLUSION: Our findings suggest that DEE exposure may contribute to genomic instability. Further investigations of environmental pollutants, Alu copy number and carcinogenesis are warranted.

Shorter Treatment-Naïve Leukocyte Telomere Length is Associated with Poorer Overall Survival of Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Critically shortened telomeres contribute to chromosomal instability and neoplastic transformation and are associated with early death of patients with certain cancer types. Shorter leukocyte telomere length (LTL) has been associated with higher risk for pancreatic ductal adenocarcinoma (PDAC) and might be associated also with survival of patients with PDAC. We investigated the association between treatment-naïve LTL and overall survival of patients with incident PDAC. METHODS: The study included 642 consecutively enrolled PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreas Research. Blood samples were obtained at the time of diagnosis, before the start of cancer treatment, from which LTL was assayed by qRT-PCR. LTL was first modeled as a continuous variable (per-interquartile range decrease in LTL) and then as a categorized variable (short, medium, long). Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated for overall mortality using Cox proportional hazard models. RESULTS: Shorter treatment-naïve LTL was associated with higher mortality among patients with PDAC (HRcontinuous = 1.13, 95% CI: 1.01-1.28, P = 0.03; HRshortest vs. longest LTL = 1.29, 95% CI: 1.05-1.59, P trend = 0.01). There was a difference in the association between LTL and overall mortality by tumor stage at diagnosis; resectable tumors (HRcontinuous = 0.91; 95% CI: 0.73-1.12), locally advanced tumors (HRcontinuous = 1.29; 95% CI: 1.07-1.56), and metastatic tumors (HRcontinuous = 1.17; 95% CI: 0.96-1.42), P interaction = 0.04. CONCLUSION: Shorter treatment-naïve LTL is associated with poorer overall survival of patients with incident PDAC. IMPACT: Peripheral blood LTL might be a prognostic marker for PDAC.

Germline mutation rates in young adults predict longevity and reproductive lifespan.

Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d'Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. Subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21-3.56; p = 0.008; median survival difference = 4.7 years). Fertility analyses were restricted to women whose age at last birth (ALB) was ≥ 30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.

Leukocyte Telomere Length and Its Interaction with Germline Variation in Telomere-Related Genes in Relation to Pancreatic Adenocarcinoma Risk.

BACKGROUND: Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We therefore investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate SNPs previously reported to be associated with variation in LTL. METHODS: A case-control study of 1,460 PDAC cases and 1,459 frequency-matched controls was performed using biospecimens and data from the Mayo Clinic Biospecimen Resource for Pancreas Research. Quantitative PCR was used to measure LTL and categorized into tertiles based on sex-specific control distribution. Eleven telomere-related SNPs also were genotyped. Logistic regression was used to calculate ORs and 95% confidence intervals (CI). RESULTS: Shorter peripheral blood LTL was associated with a higher risk of PDAC (ORT1vsT3 = 1.26, 95% CI = 1.03-1.54, P trend = 0.02; ORcontinuous = 1.14, 95% CI = 1.02-1.28), but the association was restricted to cases with treatment-naïve blood samples (ORT1vsT3 = 1.51, 95% CI = 1.16-1.96, P trend = 0.002; ORcontinuous = 1.25, 95% CI = 1.08-1.45) and not cases whose blood samples were collected after initiation of cancer therapy (ORT1vsT3 = 1.10, 95% CI = 0.87-1.39, P trend = 0.42; ORcontinuous = 1.08, 95% CI = 0.94-1.23). Three SNPs (TERC-rs10936599, ACYP2-rs11125529, and TERC-rs1317082) were each associated with interindividual variation in LTL among controls, but there was no evidence of effect modification by these SNPs. CONCLUSIONS: Treatment-naïve short LTL is associated with a higher risk of PDAC, and the association does not differ by germline variation in the candidate telomere-related SNPs examined. IMPACT: Peripheral blood LTL might serve as a molecular marker for risk modeling to identify persons at high risk of PDAC.

Variation in ribosomal DNA copy number is associated with lung cancer risk in a prospective cohort study.

Disruption of ribosomal DNA (rDNA) has been linked to a variety of diseases in humans, including carcinogenesis. To evaluate the associations between rDNA copy number (CN) and risk of lung cancer, we measured 5.8S and 18S rDNA CN in the peripheral blood of 229 incident lung cancer cases and 1:1 matched controls from a nested case-control study within a prospective cohort of male smokers. There was a dose-response relationship between quartiles of both 18S and 5.8S rDNA CN and risk of lung cancer (odds ratio [OR], 95% confidence interval [CI]: 18S: 1.0 [ref]; 1.2 [0.6-2.1]; 1.8 [1.0-3.4]; 2.3 [1.3-4.1; Ptrend = 0.0002; 5.8S: 1.0 [ref]; 1.6 [0.8-2.9]; 2.2 [1.1-4.2]; 2.6 [1.3-5.1]; Ptrend = 0.0001). The associations between rDNA CN and lung cancer risk were similar when excluding cases diagnosed within 5 years of follow-up, and when stratifying by heavy (>20 cigarettes per day) and light smokers (≤20 cigarettes per day). We are the first to report that rDNA CN may be associated with future risk of lung cancer. To further elucidate the relationship between rDNA and lung cancer, replication studies are needed in additional populations, particularly those that include non-smokers.

Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress.

Age-related vascular dysfunction in large elastic and resistance arteries is associated with reductions in microvascular perfusion and elevations in blood pressure. Recent evidence indicates that telomere uncapping-induced senescence in vascular cells may be an important source of oxidative stress and vascular dysfunction in aging, but the causal relationship between these processes has yet to be elucidated. To test this important unexplored hypothesis, we measured arterial senescence signaling and oxidative stress, carotid and mesenteric artery endothelium-dependent vasodilatory capacity, markers of mesenteric microvascular perfusion and endothelial glycocalyx deterioration, and blood pressure in a novel mouse model of Cre-inducible whole body Trf2 deletion and telomere uncapping. Trf2 deletion led to a 320% increase in arterial senescence signaling (P < .05). There was a concurrent 29% and 22% reduction in peak endothelium-dependent vasodilation in carotid and mesenteric arteries, respectively, as well as a 63% reduction in mesenteric microvascular endothelial glycocalyx thickness (all P ≤ .01). Mesenteric microvascular perfusion was reduced by 8% and systolic blood pressure was increased by 9% following Trf2 deletion (both P < .05). Trf2 deletion also led to a pro-oxidative arterial phenotype characterized by increased in NADPH oxidase gene expression; a 210% increase in superoxide levels that was partly dependent on NADPH oxidase activity; and an oxidative stress mediated reduction in carotid artery vasodilation (all P ≤ .05). Collectively, our findings demonstrate that induced Trf2 deletion leads to telomere uncapping, increased senescence signaling, and oxidative stress mediated functional impairments in the vasculature similar to those seen in human aging.

Leukocyte telomere length and renal cell carcinoma survival in two studies.

BACKGROUND: Leukocyte telomere length (LTL) is a potential biomarker of cancer prognosis; however, evidence for renal cell carcinoma (RCC) is inconsistent. METHODS: We investigated LTL and RCC-specific survival among 684 cases from the US kidney cancer study (USKC) and 241 cases from the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO). Leukocyte telomere length was measured by quantitative polymerase chain reaction, and hazard ratios (HRs) and 95% confidence intervals (CIs) computed using multivariable Cox models. RESULTS: Short LTL was associated with poorer disease-specific survival in both USKC (lowest vs highest quartile: HR: 2.3, 95% CI: 1.2-4.4; P for trend=0.02) and PLCO (HR: 2.4, 95% CI: 1.0-5.4; P=0.04). Among USKC cases, the association was strongest for stage-I RCC (HR: 5.5, 95% CI: 1.6-19.0; P=0.006). CONCLUSIONS: Our findings suggest that shorter LTL is an independent marker of poor RCC prognosis, particularly for stage-I disease.

Paternal and grandpaternal ages at conception and descendant telomere lengths in chimpanzees and humans.

Telomeres are repeating DNA at chromosome ends. Telomere length (TL) declines with age in most human tissues, and shorter TL is thought to accelerate senescence. In contrast, older men have sperm with longer TL; correspondingly, older paternal age at conception (PAC) predicts longer TL in offspring. This PAC-effect could be a unique form of transgenerational genetic plasticity that modifies somatic maintenance in response to cues of recent ancestral experience. The PAC-effect has not been examined in any non-human mammals. OBJECTIVES: Here, we examine the PAC-effect in chimpanzees (Pan troglodytes). The PAC-effect on TL is thought to be driven by continual production of sperm-the same process that drives increased de novo mutations with PAC. As chimpanzees have both greater sperm production and greater sperm mutation rates with PAC than humans, we predict that the PAC-effect on TL will be more pronounced in chimpanzees. Additionally we examine whether PAC predicts TL of grandchildren. MATERIALS AND METHODS: TL were measured using qPCR from DNA from blood samples from 40 captive chimpanzees and 144 humans. RESULTS: Analyses showed increasing TL with PAC in chimpanzees (p = .009) with a slope six times that in humans (p = .026). No associations between TL and grandpaternal ages were found in humans or chimpanzees-although statistical power was low. DISCUSSION: These results suggest that sperm production rates across species may be a determinant of the PAC-effect on offspring TL. This raises the possibility that sperm production rates within species may influence the TL passed on to offspring.

Age-related arterial telomere uncapping and senescence is greater in women compared with men.

Telomere uncapping increases with advancing age in human arteries and this telomere uncapping is associated with increased markers of senescence, independent of mean telomere length. However, whether there are sex specific differences in arterial telomere uncapping is unknown. We found that telomere uncapping (serine 139 phosphorylated histone γ-H2A.X in telomeres) in arteries was ~2.5 fold greater in post-menopausal women (n=17, 63±2 years) compared with pre-menopausal women (n=11, 30±2 years, p=0.02), while there was only a trend towards greater telomere uncapping in older men (n=26, 66±2 years) compared with young men (n=11, 31±2, p=0.11). Senescence markers, p53 bound to the p21 gene promoter and p21 gene expression, were 3-4 fold greater in post-menopausal compared with pre-menopausal women (p=0.01-0.02), but only 1.5-2 fold greater in older compared with young men (p=0.02-0.08). Blood glucose was related to telomere uncapping in women, while systolic blood pressure, pulse pressure and serum creatinine were related to telomere uncapping in men. Mean arterial telomere length decreased similarly in women and men with age (p<0.01). Thus, the age-related increase in arterial telomere uncapping and senescence is greater in women than men, despite similar age-related reductions in mean telomere length in both sexes.

Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study.

BACKGROUND: Atrial fibrillation (AF) diminishes quality of life and accounts for approximately one-third of all strokes. Studies have associated mitochondrial dysfunction with both AF and telomere length (TL). OBJECTIVE: The purpose of this study was to test the hypothesis of a relationship between AF and TL. METHODS: Blood was collected from consenting participants in the Intermountain Heart Collaborative Study (n = 3576) and DNA extracted. TL was determined by multiplex quantitative polymerase chain reaction, normalized to a single copy gene, and reported as telomere/single gene ratio (t/s). Patient information was extracted from Intermountain Healthcare's electronic records database. Prevalent AF was determined by discharge ICD-9 code. AF subtype (paroxysmal [Px], persistent [Ps], long-standing persistent/permanent [Pm]) was determined by chart review. RESULTS: The t/s decreased with age (P <.00001). Subjects with a history of AF (n = 379 [10.6%] had shorter telomeres (mean t/s ± SD = 0.87 ± 0.29) compared to subjects without AF (mean t/s 0.95 ± 0.32, P <.0001). The association remained after adjustment for age (P = .017) and cardiovascular risk factors (P = .016). AF subtype was determined for 277 subjects; 110 (39.7%) had Px AF, 65 (23.5%) Ps, and 102 (36.8%) Pm AF. Mean t/s did not differ between Ps, Pm, and subjects without AF (0.94 ± 0.40, 0.94 ± 0.27, and 0.95 ± 0.32, respectively). However, the mean t/s for Px (0.81 ± 0.22) was significantly shorter than for Ps (P = .026), Pm (P = .004), or subjects without AF (P <.0001). CONCLUSION: The present study supports an association between Px AF and TL. Short TL may be a previously unrecognized risk factor for AF with potential applications in diagnosis and therapy.