Sequence variation in telomerase reverse transcriptase (TERT) as a determinant of risk of cardiovascular disease: the Atherosclerosis Risk in Communities (ARIC) study

BMC Medical Genetics

Eric Boerwinkle³  Aaron R. Folsom⁴  Thomas H. Mosley⁵  Ellen W. Demerath⁴  Nora Franceschini¹  Jan Bressler² 

[1] Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, 135 Dauer Drive, Chapel Hill 27599, NC, USA;Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston 77030, TX, USA;Human Genome Sequencing Center, Baylor College of Medicine, 1 Baylor Plaza, Houston 77030, TX, USA;Division of Epidemiology and Community Health, University of Minnesota School of Public Health, 1300 South Second Street, Minneapolis 55454, MN, USA;Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson 39216, MS, USA

关键词: Cellular aging;    Cell senescence;    Telomere homeostasis;    Cerebrovascular stroke;    Myocardial infarction;    Genetic epidemiology;   

Others  :  1223216
DOI  :  10.1186/s12881-015-0194-x

 received in 2014-10-04, accepted in 2015-06-26,  发布年份 2015

【 摘 要 】

Background

Telomerase reverse transcriptase (TERT) maintains telomere ends during DNA replication by catalyzing the addition of short telomere repeats. The expression of telomerase is normally repressed in somatic cells leading to a gradual shortening of telomeres and cellular senescence with aging. Interindividual variation in leukocyte telomere length has been previously associated with susceptibility to cardiovascular disease. The aim of the present study was to determine whether six variants in the TERT gene are associated with risk of incident coronary heart disease, incident ischemic stroke, and mortality in participants in the biracial population-based Atherosclerosis Risk in Communities (ARIC) study, including rs2736100 that was found to influence mean telomere length in a genome-wide analysis.

Methods

ARIC is a prospective study of the etiology and natural history of atherosclerosis in 15,792 individuals aged 45 to 64 years at baseline in 1987–1989. Haplotype tagging SNPs in TERT were genotyped using a custom array containing nearly 49,000 SNPs in 2,100 genes associated with cardiovascular and metabolic phenotypes. Cox proportional hazards models were used to assess the association between the TERT polymorphisms and incident cardiovascular disease and mortality over a 20-year follow-up period in 8,907 whites and 3,022 African-Americans with no history of disease at the baseline examination, while individuals with prevalent cardiovascular disease were not excluded from the analyses of mortality.

Results

After adjustment for age and gender, and assuming an additive genetic model, rs2736122 and rs2853668 were nominally associated with incident coronary heart disease (hazards rate ratio = 1.20, p = 0.02, 95 % confidence interval = 1.03– 1.40) and stroke (hazards rate ratio = 1.17, p = 0.05, 95 % confidence interval = 1.00 - 1.38), respectively, in African-Americans. None of the variants was significantly associated with cardiovascular disease in white study participants or with mortality in either racial group.

Conclusions

Replication in additional population-based samples combined with genotyping of polymorphisms in other genes involved in maintenance of telomere length may help to determine whether genetic variants associated with telomere homeostasis influence the risk of cardiovascular disease in middle-aged adults.

【 授权许可】

   
2015 Bressler et al.

【 参考文献 】

• [1]Morin GB. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989; 59(3):521-529.
• [2]Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990; 345(6274):458-460.
• [3]Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC. Telomere reduction in human colorectal carcinoma and with ageing. Nature. 1990; 346(6287):866-868.
• [4]Vasa-Nicotera M, Brouilette S, Mangino M, Thompson JR, Braund P, Clemitson JR et al.. Mapping of a major locus that determines telomere length in humans. Am J Hum Genet. 2005; 76(1):147-151.
• [5]Andrew T, Aviv A, Falchi M, Surdulescu GL, Gardner JP, Lu X et al.. Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs. Am J Hum Genet. 2006; 78(3):480-486.
• [6]Serrano AL, Andres V. Telomeres and cardiovascular disease: does size matter? Circ Res. 2004; 94(5):575-584.
• [7]Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet. 2001; 358(9280):472-473.
• [8]Brouilette S, Singh RK, Thompson JR, Goodall AH, Samani NJ. White cell telomere length and risk of premature myocardial infarction. Arterioscler, Thromb, Vasc Biol. 2003; 23(5):842-846.
• [9]van der Harst P, van der Steege G, de Boer RA, Voors AA, Hall AS, Mulder MJ et al.. Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol. 2007; 49(13):1459-1464.
• [10]Jiang X, Dong M, Cheng J, Huang S, He Y, Ma K et al.. Decreased leukocyte telomere length (LTL) is associated with stroke but unlikely to be causative. PLoS One. 2013; 8(7):e68254.
• [11]Zhang W, Chen Y, Wang Y, Liu P, Zhang M, Zhang C et al.. Short telomere length in blood leucocytes contributes to the presence of atherothrombotic stroke and haemorrhagic stroke and risk of post-stroke death. Clin Sci. 2013; 125(1):27-36.
• [12]Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, Shepherd J et al.. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case–control study. Lancet. 2007; 369(9556):107-114.
• [13]Fitzpatrick AL, Kronmal RA, Gardner JP, Psaty BM, Jenny NS, Tracy RP et al.. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol. 2007; 165(1):14-21.
• [14]Zee RY, Michaud SE, Germer S, Ridker PM. Association of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case–control approach. Clinica chimica acta; international journal of clinical chemistry. 2009; 403(1–2):139-141.
• [15]Weischer M, Bojesen SE, Cawthon RM, Freiberg JJ, Tybjaerg-Hansen A, Nordestgaard BG. Short telomere length, myocardial infarction, ischemic heart disease, and early death. Arterioscler, Thromb, Vasc Biol. 2012; 32(3):822-829.
• [16]Schurks M, Prescott J, Dushkes R, De Vivo I, Rexrode KM. Telomere length and ischaemic stroke in women: a nested case–control study. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2013; 20(7):1068-1074.
• [17]Zee RY, Castonguay AJ, Barton NS, Ridker PM. Relative leukocyte telomere length and risk of incident ischemic stroke in men: a prospective, nested case–control approach. Rejuvenation Res. 2010; 13(4):411-414.
• [18]Njajou OT, Cawthon RM, Damcott CM, Wu SH, Ott S, Garant MJ et al.. Telomere length is paternally inherited and is associated with parental lifespan. Proc Natl Acad Sci U S A. 2007; 104(29):12135-12139.
• [19]Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003; 361(9355):393-395.
• [20]Fitzpatrick AL, Kronmal RA, Kimura M, Gardner JP, Psaty BM, Jenny NS et al.. Leukocyte telomere length and mortality in the Cardiovascular Health Study. J Gerontol A Biol Sci Med Sci. 2011; 66(4):421-429.
• [21]Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL et al.. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013; 45(4):422-427.
• [22]Roberts JD, Dewland TA, Longoria J, Fitzpatrick AL, Ziv E, Hu D et al.. Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging. Circ Arrhythm Electrophysiol. 2014; 7(6):1026-1032.
• [23]Rosamond WD, Folsom AR, Chambless LE, Wang CH, McGovern PG, Howard G et al.. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke; a journal of cerebral circulation. 1999; 30(4):736-743.
• [24]The ARIC investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. American journal of epidemiology 1989, 129(4):687–702.
• [25]Musunuru K, Lettre G, Young T, Farlow DN, Pirruccello JP, Ejebe KG et al.. Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet. 2010; 3(3):267-275.
• [26]Keating BJ, Tischfield S, Murray SS, Bhangale T, Price TS, Glessner JT et al.. Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS One. 2008; 3(10):e3583.
• [27]International HapMap C, Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL et al.. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007; 449(7164):851-861.
• [28]Crawford DC, Carlson CS, Rieder MJ, Carrington DP, Yi Q, Smith JD et al.. Haplotype diversity across 100 candidate genes for inflammation, lipid metabolism, and blood pressure regulation in two populations. Am J Hum Genet. 2004; 74(4):610-622.
• [29]Bressler J, Kao WH, Pankow JS, Boerwinkle E. Risk of type 2 diabetes and obesity is differentially associated with variation in FTO in whites and African-Americans in the ARIC study. PLoS One. 2010; 5(5):e10521.
• [30]Morrison AC, Bray MS, Folsom AR, Boerwinkle E. ADD1 460 W allele associated with cardiovascular disease in hypertensive individuals. Hypertension. 2002; 39(6):1053-1057.
• [31]Siedel J, Hagele EO, Ziegenhorn J, Wahlefeld AW. Reagent for the enzymatic determination of serum total cholesterol with improved lipolytic efficiency. Clin Chem. 1983; 29(6):1075-1080.
• [32]Warnick GR, Benderson J, Albers JJ. Dextran sulfate-Mg2+ precipitation procedure for quantitation of high-density-lipoprotein cholesterol. Clin Chem. 1982; 28(6):1379-1388.
• [33]Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21(2):263-265.
• [34]Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994; 81(3):515-526.
• [35]Hintze J. Power Analysis and Sample Size (PASS) 11. NCSS, LLC, Kaysville UT; 2011.
• [36]Moslehi J, DePinho RA, Sahin E. Telomeres and mitochondria in the aging heart. Circ Res. 2012; 110(9):1226-1237.
• [37]Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB et al.. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998; 279(5349):349-352.
• [38]Samper E, Flores JM, Blasco MA. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep. 2001; 2(9):800-807.
• [39]Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC et al.. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011; 469(7328):102-106.
• [40]Oh H, Taffet GE, Youker KA, Entman ML, Overbeek PA, Michael LH et al.. Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Proc Natl Acad Sci U S A. 2001; 98(18):10308-10313.
• [41]Zee RY, Ridker PM, Chasman DI. Genetic variants in eleven telomere-associated genes and the risk of incident cardio/cerebrovascular disease: The Women’s Genome Health Study. Clinica chimica acta; international journal of clinical chemistry. 2011; 412(1–2):199-202.
• [42]Lin PI, Vance JM, Pericak-Vance MA, Martin ER. No gene is an island: the flip-flop phenomenon. Am J Hum Genet. 2007; 80(3):531-538.
• [43]Preuss M, Konig IR, Thompson JR, Erdmann J, Absher D, Assimes TL et al.. Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: A Genome-wide association meta-analysis involving more than 22 000 cases and 60 000 controls. Circ Cardiovasc Genet. 2010; 3(5):475-483.
• [44]Frenck RW, Blackburn EH, Shannon KM. The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci U S A. 1998; 95(10):5607-5610.
• [45]Melk A, Ramassar V, Helms LM, Moore R, Rayner D, Solez K et al.. Telomere shortening in kidneys with age. Journal of the American Society of Nephrology : JASN. 2000; 11(3):444-453.
• [46]Benetos A, Okuda K, Lajemi M, Kimura M, Thomas F, Skurnick J et al.. Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity. Hypertension. 2001; 37(2 Pt 2):381-385.
• [47]Ishii A, Nakamura K, Kishimoto H, Honma N, Aida J, Sawabe M et al.. Telomere shortening with aging in the human pancreas. Exp Gerontol. 2006; 41(9):882-886.
• [48]Bischoff C, Petersen HC, Graakjaer J, Andersen-Ranberg K, Vaupel JW, Bohr VA et al.. No association between telomere length and survival among the elderly and oldest old. Epidemiology. 2006; 17(2):190-194.
• [49]Harris SE, Deary IJ, MacIntyre A, Lamb KJ, Radhakrishnan K, Starr JM et al.. The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people. Neurosci Lett. 2006; 406(3):260-264.
• [50]Njajou OT, Hsueh WC, Blackburn EH, Newman AB, Wu SH, Li R et al.. Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study. J Gerontol A Biol Sci Med Sci. 2009; 64(8):860-864.
• [51]Levy D, Neuhausen SL, Hunt SC, Kimura M, Hwang SJ, Chen W et al.. Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci U S A. 2010; 107(20):9293-9298.
• [52]Burnett-Hartman AN, Fitzpatrick AL, Kronmal RA, Psaty BM, Jenny NS, Bis JC et al.. Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study. Mech Ageing Dev. 2012; 133(5):275-281.
• [53]Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF et al.. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005; 366(9486):662-664.
• [54]Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, Beveridge AJ et al.. Common variants near TERC are associated with mean telomere length. Nat Genet. 2010; 42(3):197-199.
• [55]Mangino M, Hwang SJ, Spector TD, Hunt SC, Kimura M, Fitzpatrick AL et al.. Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. Hum Mol Genet. 2012; 21(24):5385-5394.