@article {922, title = {Leukocyte telomere length and cardiovascular disease in the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {165}, year = {2007}, month = {2007 Jan 01}, pages = {14-21}, abstract = {

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age = 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio = 3.08, 95\% confidence interval: 1.22, 7.73) and stroke (hazard ratio = 3.22, 95\% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.

}, keywords = {Aged, Cardiovascular Diseases, DNA, Female, Humans, Inflammation, Leukocytes, Male, Myocardial Infarction, Oxidative Stress, Pilot Projects, Polymorphism, Restriction Fragment Length, Risk, Risk Assessment, Risk Factors, Telomere}, issn = {0002-9262}, doi = {10.1093/aje/kwj346}, author = {Fitzpatrick, Annette L and Kronmal, Richard A and Gardner, Jeffrey P and Psaty, Bruce M and Jenny, Nancy S and Tracy, Russell P and Walston, Jeremy and Kimura, Masyuki and Aviv, Abraham} } @article {1088, title = {Insulin-like growth factors and leukocyte telomere length: the cardiovascular health study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {64}, year = {2009}, month = {2009 Nov}, pages = {1103-6}, abstract = {

The insulin-like growth factor (IGF) axis may affect immune cell replicative potential and telomere dynamics. Among 551 adults 65 years and older, leukocyte telomere length (LTL), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1, IGFBP-3) were measured. Multivariate linear regression was used to model the association of LTL with IGF-1 and IGFBPs, while controlling for confounding and increasing precision by adjusting for covariates. We observed a significant association between higher IGF-1 and longer LTL after adjustment for age, sex, race, smoking status, body mass index, hypertension, diabetes, and serum lipids. The results suggested an increase of .08 kb in LTL for each standard deviation increase of IGF-1 (p = .04). IGFBP-1 and IGFBP-3 were not significantly associated with LTL. High IGF-1 may be an independent predictor of longer LTL, consistent with prior evidence suggesting a role for IGF-1 in mechanisms relating to telomere maintenance.

}, keywords = {Aged, Aging, Cross-Sectional Studies, Female, Humans, Insulin-Like Growth Factor Binding Protein 1, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Leukocytes, Linear Models, Male, Sex Characteristics, Telomere}, issn = {1758-535X}, doi = {10.1093/gerona/glp036}, author = {Kaplan, Robert C and Fitzpatrick, Annette L and Pollak, Michael N and Gardner, Jeffrey P and Jenny, Nancy S and McGinn, Aileen P and Kuller, Lewis H and Strickler, Howard D and Kimura, Masayuki and Psaty, Bruce M and Aviv, Abraham} } @article {1192, title = {Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.}, journal = {Proc Natl Acad Sci U S A}, volume = {107}, year = {2010}, month = {2010 May 18}, pages = {9293-8}, abstract = {

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

}, keywords = {Cohort Studies, Genome-Wide Association Study, Genotype, Humans, Leukocytes, Polymorphism, Single Nucleotide, Receptors, CXCR4, Telomere, Telomere-Binding Proteins}, issn = {1091-6490}, doi = {10.1073/pnas.0911494107}, author = {Levy, Daniel and Neuhausen, Susan L and Hunt, Steven C and Kimura, Masayuki and Hwang, Shih-Jen and Chen, Wei and Bis, Joshua C and Fitzpatrick, Annette L and Smith, Erin and Johnson, Andrew D and Gardner, Jeffrey P and Srinivasan, Sathanur R and Schork, Nicholas and Rotter, Jerome I and Herbig, Utz and Psaty, Bruce M and Sastrasinh, Malinee and Murray, Sarah S and Vasan, Ramachandran S and Province, Michael A and Glazer, Nicole L and Lu, Xiaobin and Cao, Xiaojian and Kronmal, Richard and Mangino, Massimo and Soranzo, Nicole and Spector, Tim D and Berenson, Gerald S and Aviv, Abraham} } @article {1265, title = {Leukocyte telomere length and mortality in the Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {66}, year = {2011}, month = {2011 Apr}, pages = {421-9}, abstract = {

BACKGROUND: Leukocyte telomere length (LTL) is related to diseases of aging, but studies of mortality have been inconsistent.

METHODS: We evaluated LTL in relation to total mortality and specific cause of death in 1,136 participants of the Cardiovascular Health Study who provided blood samples in 1992-1993 and survived through 1997-1998. LTL was measured by Southern blots of the terminal restriction fragments. Cause of death was classified by a committee of physicians reviewing death certificates, medical records, and informant interviews.

RESULTS: A total of 468 (41.2\%) deaths occurred over 6.1 years of follow-up in participants with mean age of 73.9 years (SD 4.7), 65.4\% female, and 14.8\% African American. Although increased age and male gender were associated with shorter LTLs, African Americans had significantly longer LTLs independent of age and sex (p < .001). Adjusted for age, sex, and race, persons with the shortest quartile of LTL were 60\% more likely to die during follow-up than those within the longest quartile (hazard ratio: 1.61, 95\% confidence interval: 1.22-2.12, p = .001). The association remained after adjustment for cardiovascular disease risk factors. Evaluations of cause of death found LTL to be related to deaths due to an infectious disease etiology (hazard ratio: 2.80, 95\% confidence interval: 1.32-5.94, p = .007), whereas a borderline association was found for cardiac deaths (hazard ratio: 1.82, 95\% confidence interval: 0.95-3.49, p = .07) in adjusted models. Risk estimates for deaths due to cancer, dementia, and ischemic stroke were not significant.

CONCLUSION: These data weakly corroborate prior findings of associations between LTL and mortality in the elderly.

}, keywords = {Aged, Aged, 80 and over, Aging, Body Mass Index, Cardiovascular Diseases, Cause of Death, Comorbidity, Coronary Disease, Diabetes Mellitus, Female, Humans, Hypertension, Leukocytes, Longitudinal Studies, Male, Prospective Studies, Smoking, Stroke, Telomere}, issn = {1758-535X}, doi = {10.1093/gerona/glq224}, author = {Fitzpatrick, Annette L and Kronmal, Richard A and Kimura, Masayuki and Gardner, Jeffrey P and Psaty, Bruce M and Jenny, Nancy S and Tracy, Russell P and Hardikar, Sheetal and Aviv, Abraham} } @article {1328, title = {Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study.}, journal = {J Gerontol A Biol Sci Med Sci}, volume = {67}, year = {2012}, month = {2012 Apr}, pages = {409-16}, abstract = {

BACKGROUND: Most studies of leukocyte telomere length (LTL) focus on diagnosed disease in one system. A more encompassing depiction of health is disease burden, defined here as the sum of noninvasively measured markers of structure or function in different organ systems. We determined if (a) shorter LTL is associated with greater age-related disease burden and (b) shorter LTL is less strongly associated with disease in individual systems or diagnosed chronic conditions (cardiovascular disease, stroke, pulmonary disease, diabetes, kidney disease, arthritis, or depression).

METHODS: LTL was measured by Southern blots of terminal restriction fragment length. Age-related disease was measured noninvasively and included carotid intima-media thickness, lung vital capacity, white matter grade, cystatin-C, and fasting glucose; each graded 0 (best tertile), 1 (middle tertile), or 2 (worst tertile) and summed (0 to 10) to estimate disease burden. Of 419 participants randomly selected for LTL measurement, 236 had disease burden assessed (mean [SD] age 74.2 [4.9] years, 42.4\% male, 86.8\% white, and 13.2\% black).

RESULTS: Mean (SD) LTL was 6,312 (615) bp, and disease score was 4.7 (2.1) points. An SD higher disease score (β [SE] = -132 [47] bp, p < .01), age (β [SE] = -107 [46], p = .02) or carotid thickness (β [SE] = -95 [40] bp, p = .02) was associated with shorter LTL, but diagnosed conditions or number of conditions were not associated with LTL. Disease score attenuated the effect of age on LTL by 35\%.

CONCLUSION: LTL was associated with a characterization of age-related disease burden across multiple physiologic systems, which was comparable to, but independent of, its association with age.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cardiovascular Diseases, Carotid Intima-Media Thickness, Chronic Disease, Cystatin C, European Continental Ancestry Group, Female, Humans, Leukocytes, Lung, Male, Middle Aged, Telomere Homeostasis}, issn = {1758-535X}, doi = {10.1093/gerona/glr173}, author = {Sanders, Jason L and Fitzpatrick, Annette L and Boudreau, Robert M and Arnold, Alice M and Aviv, Abraham and Kimura, Masayuki and Fried, Linda F and Harris, Tamara B and Newman, Anne B} } @article {1375, title = {Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study.}, journal = {Mech Ageing Dev}, volume = {133}, year = {2012}, month = {2012 May}, pages = {275-81}, abstract = {

Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages >=65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95\% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r(2)=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95\% CI: 0.5-0.9 (CC vs. AC) and HR=0.5; 95\% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR=1.0; 95\% CI: 0.7-1.3 (CC vs. AC) and HR=1.7; 95\% CI: 0.8-3.6 (CC vs. AA) (P-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Female, Humans, Leukocytes, Male, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Risk, RNA, Sex Factors, Telomerase, Telomere}, issn = {1872-6216}, doi = {10.1016/j.mad.2012.03.002}, author = {Burnett-Hartman, Andrea N and Fitzpatrick, Annette L and Kronmal, Richard A and Psaty, Bruce M and Jenny, Nancy S and Bis, Josh C and Tracy, Russ P and Kimura, Masayuki and Aviv, Abraham} } @article {6293, title = {Leukocyte telomere length and age at menopause.}, journal = {Epidemiology}, volume = {25}, year = {2014}, month = {2014 Jan}, pages = {139-46}, abstract = {

BACKGROUND: Telomere length is a marker of cellular aging that varies with the individual, is inherited, and is highly correlated across somatic cell types within persons. Interindividual variability of telomere length may partly explain differences in reproductive aging rates. We examined whether leukocyte telomere length was associated with menopausal age.

METHODS: We evaluated the relationship between leukocyte telomere length and age at natural menopause in 486 white women >=65 years of age. We fit linear regression models adjusted for age, income, education, body mass index, physical activity, smoking, and alcohol intake. We repeated the analysis in women with surgical menopause. We also performed sensitivity analyses excluding women (1) with unilateral oophorectomy, (2) who were nulliparous, or (3) reporting menopausal age <40 years, among other exclusions.

RESULTS: For every 1-kb increase in leukocyte telomere length, average age at natural menopause increased by 10.2 months (95\% confidence interval = 1.3 to 19.0). There was no association among 179 women reporting surgical menopause. In all but one sensitivity analysis, the association between leukocyte telomere length and age at menopause became stronger. However, when excluding women with menopausal age <40 years, the association decreased to 7.5 months (-0.4 to 15.5).

CONCLUSIONS: Women with the longest leukocyte telomere length underwent menopause 3 years later than those with the shortest leukocyte telomere length. If an artifact, an association would likely also have been observed in women with surgical menopause. If these results are replicated, leukocyte telomere length may prove to be a useful predictor of age at menopause.

}, keywords = {Adult, Age of Onset, Aged, Aging, Alcohol Drinking, Body Mass Index, Educational Status, European Continental Ancestry Group, Female, Humans, Leukocytes, Linear Models, Menopause, Middle Aged, Motor Activity, Smoking, Telomere}, issn = {1531-5487}, doi = {10.1097/EDE.0000000000000017}, author = {Gray, Kristen E and Schiff, Melissa A and Fitzpatrick, Annette L and Kimura, Masayuki and Aviv, Abraham and Starr, Jacqueline R} } @article {6594, title = {Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Dec}, pages = {1026-32}, abstract = {

BACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95\% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95\% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 {\textpm} 0.20 versus 1.02 {\textpm} 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.

CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.

}, keywords = {Age Factors, Aged, Aging, Atrial Fibrillation, California, Cardiac Surgical Procedures, Cellular Senescence, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Humans, Incidence, Leukocytes, Male, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Telomerase, Telomere, Time Factors}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001781}, author = {Roberts, Jason D and Dewland, Thomas A and Longoria, James and Fitzpatrick, Annette L and Ziv, Elad and Hu, Donglei and Lin, Jue and Glidden, David V and Psaty, Bruce M and Burchard, Esteban G and Blackburn, Elizabeth H and Olgin, Jeffrey E and Heckbert, Susan R and Marcus, Gregory M} } @article {6573, title = {Trans-ethnic meta-analysis of white blood cell phenotypes.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Dec 20}, pages = {6944-60}, abstract = {

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

}, keywords = {African Americans, Asian Continental Ancestry Group, Bayes Theorem, European Continental Ancestry Group, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Leukocyte Count, Leukocytes, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1460-2083}, doi = {10.1093/hmg/ddu401}, author = {Keller, Margaux F and Reiner, Alexander P and Okada, Yukinori and van Rooij, Frank J A and Johnson, Andrew D and Chen, Ming-Huei and Smith, Albert V and Morris, Andrew P and Tanaka, Toshiko and Ferrucci, Luigi and Zonderman, Alan B and Lettre, Guillaume and Harris, Tamara and Garcia, Melissa and Bandinelli, Stefania and Qayyum, Rehan and Yanek, Lisa R and Becker, Diane M and Becker, Lewis C and Kooperberg, Charles and Keating, Brendan and Reis, Jared and Tang, Hua and Boerwinkle, Eric and Kamatani, Yoichiro and Matsuda, Koichi and Kamatani, Naoyuki and Nakamura, Yusuke and Kubo, Michiaki and Liu, Simin and Dehghan, Abbas and Felix, Janine F and Hofman, Albert and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Franco, Oscar H and Longo, Dan L and Singleton, Andrew B and Psaty, Bruce M and Evans, Michelle K and Cupples, L Adrienne and Rotter, Jerome I and O{\textquoteright}Donnell, Christopher J and Takahashi, Atsushi and Wilson, James G and Ganesh, Santhi K and Nalls, Mike A} } @article {6817, title = {DCAF4, a novel gene associated with leucocyte telomere length.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Mar}, pages = {157-62}, abstract = {

BACKGROUND: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR).

RESULTS: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4{\texttimes}10(-10)) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1{\texttimes}10(-3) and 2{\texttimes}10(-3), respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds (p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly over-represented for melanoma at p values ranging from 1.97{\texttimes}10(-169) to 3.42{\texttimes}10(-24).

CONCLUSIONS: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

}, keywords = {Alleles, Carrier Proteins, Gene Expression Regulation, Genome-Wide Association Study, Humans, Leukocytes, Melanoma, Risk Factors, Telomere, Telomere Homeostasis}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2014-102681}, author = {Mangino, Massimo and Christiansen, Lene and Stone, Rivka and Hunt, Steven C and Horvath, Kent and Eisenberg, Dan T A and Kimura, Masayuki and Petersen, Inge and Kark, Jeremy D and Herbig, Utz and Reiner, Alex P and Benetos, Athanase and Codd, Veryan and Nyholt, Dale R and Sinnreich, Ronit and Christensen, Kaare and Nassar, Hisham and Hwang, Shih-Jen and Levy, Daniel and Bataille, Veronique and Fitzpatrick, Annette L and Chen, Wei and Berenson, Gerald S and Samani, Nilesh J and Martin, Nicholas G and Tishkoff, Sarah and Schork, Nicholas J and Kyvik, Kirsten Ohm and Dalg{\r a}rd, Christine and Spector, Timothy D and Aviv, Abraham} } @article {6743, title = {Physical Activity, Physical Fitness, and Leukocyte Telomere Length: The Cardiovascular Health Study.}, journal = {Med Sci Sports Exerc}, volume = {47}, year = {2015}, month = {2015 Dec}, pages = {2525-34}, abstract = {

INTRODUCTION: The influence of physical activity (PA) and physical fitness (PF) at older ages on changes in telomere length (TL)--repetitive DNA sequences that may mark biologic aging--is not well-established. Few prior studies (mainly cross-sectional) have been conducted in older adults, and few studies have evaluated PF.

METHODS: We investigated cross-sectional and prospective associations of PA and PF with leukocyte TL among 582 older adults (mean {\textpm} SD age, 73 {\textpm} 5 yr at baseline) in the Cardiovascular Health Study, with serial TL measures and PA and PF assessed multiple times. Cross-sectional associations were assessed using multivariable repeated-measures regression, in which cumulatively averaged PA and PF measures were related to TL. Longitudinal analyses assessed cumulatively averaged PA and PF against later changes in TL, and changes in cumulatively averaged PA and PF against changes in TL.

RESULTS: Cross-sectionally, greater walking distance and chair test performance, but not other PA and PF measures, were each associated with longer TL (P trend = 0.007 and 0.04, respectively). In longitudinal analyses, no significant associations of baseline PA and PF with change in TL were observed. In contrast, changes in leisure-time activity and chair test performance were each inversely associated with changes in TL.

CONCLUSIONS: Cross-sectional analyses suggest that greater PA and PF are associated with longer TL. Prospective analyses show that changes in PA and PF are associated with differences in changes in TL. Even later in life, changes in certain PA and PF measures are associated with changes in TL, suggesting that leisure-time activity and fitness could reduce leukocyte telomere attrition among older adults.

}, keywords = {Aged, Aging, Cross-Sectional Studies, Exercise Test, Female, Hand Strength, Humans, Leukocytes, Male, Motor Activity, Physical Fitness, Prospective Studies, Telomere Homeostasis, Walking}, issn = {1530-0315}, doi = {10.1249/MSS.0000000000000720}, author = {Soares-Miranda, Luisa and Imamura, Fumiaki and Siscovick, David and Jenny, Nancy Swords and Fitzpatrick, Annette L and Mozaffarian, Dariush} } @article {8507, title = {Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.}, journal = {Circulation}, volume = {140}, year = {2019}, month = {2019 08 20}, pages = {645-657}, abstract = {

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67\% women, 35\% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

}, keywords = {Adult, Aged, Cohort Studies, Coronary Disease, CpG Islands, DNA Methylation, Europe, Female, Genome-Wide Association Study, Humans, Incidence, Leukocytes, Male, Middle Aged, Myocardial Infarction, Population Groups, Prognosis, Prospective Studies, Risk, United States}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.039357}, author = {Agha, Golareh and Mendelson, Michael M and Ward-Caviness, Cavin K and Joehanes, Roby and Huan, Tianxiao and Gondalia, Rahul and Salfati, Elias and Brody, Jennifer A and Fiorito, Giovanni and Bressler, Jan and Chen, Brian H and Ligthart, Symen and Guarrera, Simonetta and Colicino, Elena and Just, Allan C and Wahl, Simone and Gieger, Christian and Vandiver, Amy R and Tanaka, Toshiko and Hernandez, Dena G and Pilling, Luke C and Singleton, Andrew B and Sacerdote, Carlotta and Krogh, Vittorio and Panico, Salvatore and Tumino, Rosario and Li, Yun and Zhang, Guosheng and Stewart, James D and Floyd, James S and Wiggins, Kerri L and Rotter, Jerome I and Multhaup, Michael and Bakulski, Kelly and Horvath, Steven and Tsao, Philip S and Absher, Devin M and Vokonas, Pantel and Hirschhorn, Joel and Fallin, M Daniele and Liu, Chunyu and Bandinelli, Stefania and Boerwinkle, Eric and Dehghan, Abbas and Schwartz, Joel D and Psaty, Bruce M and Feinberg, Andrew P and Hou, Lifang and Ferrucci, Luigi and Sotoodehnia, Nona and Matullo, Giuseppe and Peters, Annette and Fornage, Myriam and Assimes, Themistocles L and Whitsel, Eric A and Levy, Daniel and Baccarelli, Andrea A} } @article {8914, title = {Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 10 07}, pages = {1836-1851}, abstract = {

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

}, keywords = {Asthma, Biomarkers, Dermatitis, Atopic, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Leukocytes, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proteome, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, United Kingdom, United States, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.08.007}, author = {Mikhaylova, Anna V and McHugh, Caitlin P and Polfus, Linda M and Raffield, Laura M and Boorgula, Meher Preethi and Blackwell, Thomas W and Brody, Jennifer A and Broome, Jai and Chami, Nathalie and Chen, Ming-Huei and Conomos, Matthew P and Cox, Corey and Curran, Joanne E and Daya, Michelle and Ekunwe, Lynette and Glahn, David C and Heard-Costa, Nancy and Highland, Heather M and Hobbs, Brian D and Ilboudo, Yann and Jain, Deepti and Lange, Leslie A and Miller-Fleming, Tyne W and Min, Nancy and Moon, Jee-Young and Preuss, Michael H and Rosen, Jonathon and Ryan, Kathleen and Smith, Albert V and Sun, Quan and Surendran, Praveen and de Vries, Paul S and Walter, Klaudia and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Zhong, Xue and Abecasis, Goncalo R and Almasy, Laura and Barnes, Kathleen C and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Chavan, Sameer and Cho, Michael H and Choquet, Helene and Correa, Adolfo and Cox, Nancy and DeMeo, Dawn L and Faraday, Nauder and Fornage, Myriam and Gerszten, Robert E and Hou, Lifang and Johnson, Andrew D and Jorgenson, Eric and Kaplan, Robert and Kooperberg, Charles and Kundu, Kousik and Laurie, Cecelia A and Lettre, Guillaume and Lewis, Joshua P and Li, Bingshan and Li, Yun and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani and Meyers, Deborah A and Mitchell, Braxton D and Morrison, Alanna C and Ngo, Debby and Nickerson, Deborah A and Nongmaithem, Suraj and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Ortega, Victor E and Pankratz, Nathan and Perry, James A and Psaty, Bruce M and Rich, Stephen S and Soranzo, Nicole and Rotter, Jerome I and Silverman, Edwin K and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Thornton, Timothy A and Vasan, Ramachandran S and Zein, Joe and Mathias, Rasika A and Reiner, Alexander P and Auer, Paul L} }