Journal of Molecular Medicine

, Volume 90, Issue 9, pp 1059–1067 | Cite as

Genetic variants implicated in telomere length associated with left ventricular function in patients with hypertension and cardiac organ damage

  • Matthias Huber
  • Andras Treszl
  • Markus Wehland
  • Ingke Winther
  • Irina Zergibel
  • Rona Reibis
  • Juliane Bolbrinker
  • Monika Stoll
  • Gilbert Schönfelder
  • Karl Wegscheider
  • Heinz Völler
  • Reinhold Kreutz
Original Article

Abstract

Telomere length has emerged as a biological correlate for ageing, which in turn is a risk factor for the manifestation of cardiovascular diseases. This study investigated the relation between leucocyte telomere length (LTL) and its genetic background to cardiac structure and function in patients with arterial hypertension. We analysed a cohort of 1,106 treated hypertensive patients (83.3% males; mean age, 57.9 ± 9.8 years) with an ejection fraction (EF) over 40% and documented cardiovascular disease or target organ damage. LTL and genotypes of single nucleotide polymorphisms (SNPs), previously implicated in LTL, were determined by real-time PCR. The mean left ventricular mass index (LVMI) and EF were 51.8 ± 21.0 g/H2.7 and 61.1 ± 9.6%, respectively. In multivariate adjusted analysis, a 1.5-fold LTL was positively related with a 2.2% increase of LVMI (CI = 0.1% to 4.2%, p = 0.044) and an absolute increase in EF of 0.6% (CI = 0.1% to 1.1%, p = 0.028). One SNP near TERC (rs16847897) showed a significant absolute difference in EF dependent on allele status (rs16847897, G allele 2.7%; CI = 0.7% to 4.6%; praw = 0.008, pmt = 0.048, after adjustment for multiple testing). This applied also for two SNPs in BICD1 (rs2630578, C allele −1.8%; CI = −2.8% to −0.7%; praw = 0.002, pmt = 0.018; rs1151026, G allele −1.9%, CI = −3.0% to −0.8%; praw < 0.001, pmt = 0.002) with the extension that a frequent haplotype in BICD1 showed an absolute −1.8% (CI = −3.0% to −0.7%; praw = 0.002, pmt = 0.008) lower EF compared with those lacking this haplotype. Our results point to a role of genetic variants recently implicated in LTL for left ventricular function in hypertensive patients.

Keywords

Ageing Cardiac output Echocardiography Genetics Hypertension Clinical research Heart 

Notes

Acknowledgements

We are grateful to all physicians, nurses and patients from the participating centres (listed in the Appendix online). We are particularly grateful to H. Buhlert and K. Stolze who were responsible for central data management and to K. Kossatz for excellent technical assistance. This work was supported by a grant from the Bundesministerium für Bildung und Forschung, Nationales Genomforschungsnetz, Herzkreislaufnetz in NGFNplus (grant number 01GS0839), Germany.

Conflicts of interest

The authors declare no conflicts of interest.

Supplementary material

109_2012_874_MOESM1_ESM.doc (1.2 mb)
ESM 1(DOC 1197 kb)

References

  1. 1.
    Ruilope LM, Schmieder RE (2008) Left ventricular hypertrophy and clinical outcomes in hypertensive patients. Am J Hypertens 21(5):500–508PubMedCrossRefGoogle Scholar
  2. 2.
    Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636PubMedCrossRefGoogle Scholar
  3. 3.
    Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH (2001) Telomere shortening in atherosclerosis. Lancet 358(9280):472–473PubMedCrossRefGoogle Scholar
  4. 4.
    Demissie S, Levy D, Benjamin EJ, Cupples LA, Gardner JP, Herbert A, Kimura M, Larson MG, Meigs JB, Keaney JF et al (2006) Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell 5(4):325–330PubMedCrossRefGoogle Scholar
  5. 5.
    Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, Shepherd J, Packard CJ, Samani NJ (2007) Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case–control study. Lancet 369(9556):107–114PubMedCrossRefGoogle Scholar
  6. 6.
    van der Harst P, de Boer RA, van Veldhuisen DJ (2009) The Nobel Prize for medicine for telomere biology and relevance to heart failure research. Eur J Heart Fail 11(12):1113–1115PubMedCrossRefGoogle Scholar
  7. 7.
    Vasan RS, Demissie S, Kimura M, Cupples LA, White C, Gardner JP, Cao X, Levy D, Benjamin EJ, Aviv A (2009) Association of leukocyte telomere length with echocardiographic left ventricular mass: the Framingham heart study. Circulation 120(13):1195–1202PubMedCrossRefGoogle Scholar
  8. 8.
    Kuznetsova T, Codd V, Brouilette S, Thijs L, Gonzalez A, Jin Y, Richart T, van der Harst P, Diez J, Staessen JA et al (2010) Association between left ventricular mass and telomere length in a population study. Am J Epidemiol 172(4):440–450PubMedCrossRefGoogle Scholar
  9. 9.
    Verdecchia P, Angeli F, Achilli P, Castellani C, Broccatelli A, Gattobigio R, Cavallini C (2007) Echocardiographic left ventricular hypertrophy in hypertension: marker for future events or mediator of events? Curr Opin Cardiol 22(4):329–334PubMedCrossRefGoogle Scholar
  10. 10.
    Collerton J, Martin-Ruiz C, Kenny A, Barrass K, von Zglinicki T, Kirkwood T, Keavney B (2007) Telomere length is associated with left ventricular function in the oldest old: the Newcastle 85+ study. Eur Heart J 28(2):172–176PubMedCrossRefGoogle Scholar
  11. 11.
    Spyridopoulos I, Hoffmann J, Aicher A, Brummendorf TH, Doerr HW, Zeiher AM, Dimmeler S (2009) Accelerated telomere shortening in leukocyte subpopulations of patients with coronary heart disease: role of cytomegalovirus seropositivity. Circulation 120(14):1364–1372PubMedCrossRefGoogle Scholar
  12. 12.
    Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, Beveridge AJ, Rafelt S, Moore J, Nelson C, Soranzo N et al (2010) Common variants near TERC are associated with mean telomere length. Nat Genet 42(3):197–199PubMedCrossRefGoogle Scholar
  13. 13.
    Mangino M, Brouilette S, Braund P, Tirmizi N, Vasa-Nicotera M, Thompson JR, Samani NJ (2008) A regulatory SNP of the BICD1 gene contributes to telomere length variation in humans. Hum Mol Genet 17(16):2518–2523PubMedCrossRefGoogle Scholar
  14. 14.
    Mangino M, Richards JB, Soranzo N, Zhai G, Aviv A, Valdes AM, Samani NJ, Deloukas P, Spector TD (2009) A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length. J Med Genet 46(7):451–454PubMedCrossRefGoogle Scholar
  15. 15.
    Volinia S, Dhand R, Vanhaesebroeck B, MacDougall LK, Stein R, Zvelebil MJ, Domin J, Panaretou C, Waterfield MD (1995) A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J 14(14):3339–3348PubMedGoogle Scholar
  16. 16.
    Madonna R, De CR, Willerson JT, Geng YJ (2011) Biologic function and clinical potential of telomerase and associated proteins in cardiovascular tissue repair and regeneration. Eur Heart J 32(10):1190–1196PubMedCrossRefGoogle Scholar
  17. 17.
    Martinez P, Blasco MA (2011) Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer 11(3):161–176PubMedCrossRefGoogle Scholar
  18. 18.
    Harata M, Nishimori K, Hatta S (2001) Identification of two cDNAs for human actin-related proteins (Arps) that have remarkable similarity to conventional actin. Biochim Biophys Acta 1522(2):130–133PubMedCrossRefGoogle Scholar
  19. 19.
    Alliel PM, Seddiqi N, Goudou D, Cifuentes-Diaz C, Romero N, Velasco E, Rieger F, Perin JP (2000) Myoneurin, a novel member of the BTB/POZ-zinc finger family highly expressed in human muscle. Biochem Biophys Res Commun 273(1):385–391PubMedCrossRefGoogle Scholar
  20. 20.
    Kim KH, Kim TG, Micales BK, Lyons GE, Lee Y (2007) Dynamic expression patterns of leucine-rich repeat containing protein 10 in the heart. Dev Dyn 236(8):2225–2234PubMedCrossRefGoogle Scholar
  21. 21.
    Huber M, Voller H, Jakob S, Reibis R, Do V, Bolbrinker J, Zergibel I, Schmieder RE, Treszl A, Wegscheider K et al (2010) Role of the angiotensin II type 2 receptor gene (+1675G/A) polymorphism on left ventricular hypertrophy and geometry in treated hypertensive patients. J Hypertens 28(6):1221–1229PubMedCrossRefGoogle Scholar
  22. 22.
    No authors listed (1999) 1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens 17(2):151–183Google Scholar
  23. 23.
    Cifkova R, Erdine S, Fagard R, Farsang C, Heagerty AM, Kiowski W, Kjeldsen S, Luscher T, Mallion JM, Mancia G et al (2003) Practice guidelines for primary care physicians: 2003 ESH/ESC hypertension guidelines. J Hypertens 21(10):1779–1786PubMedCrossRefGoogle Scholar
  24. 24.
    Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30(10):e47PubMedCrossRefGoogle Scholar
  25. 25.
    Lee M, Martin H, Firpo MA, Demerath EW (2011) Inverse association between adiposity and telomere length: the Fels Longitudinal Study. Am J Hum Biol 23(1):100–106PubMedCrossRefGoogle Scholar
  26. 26.
    Wong LS, Huzen J, van der Harst P, de Boer RA, Codd V, Westenbrink BD, Benus GF, Voors AA, van Gilst WH, Samani NJ et al (2010) Anaemia is associated with shorter leucocyte telomere length in patients with chronic heart failure. Eur J Heart Fail 12(4):348–353PubMedCrossRefGoogle Scholar
  27. 27.
    Pavesi E, Avondo F, Aspesi A, Quarello P, Rocci A, Vimercati C, Pigullo S, Dufour C, Ramenghi U, Dianzani I (2009) Analysis of telomeres in peripheral blood cells from patients with bone marrow failure. Pediatr Blood Cancer 53(3):411–416PubMedCrossRefGoogle Scholar
  28. 28.
    Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM (2007) Statistics in medicine–reporting of subgroup analyses in clinical trials. N Engl J Med 357(21):2189–2194PubMedCrossRefGoogle Scholar
  29. 29.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a new and powerful approach to multiple testing. Journal of the Royal Statistical Society B 57:1289–1300Google Scholar
  30. 30.
    de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH (1995) Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 25(5):1056–1062PubMedCrossRefGoogle Scholar
  31. 31.
    Arnett DK, Li N, Tang W, Rao DC, Devereux RB, Claas SA, Kraemer R, Broeckel U (2009) Genome-wide association study identifies single-nucleotide polymorphism in KCNB1 associated with left ventricular mass in humans: the HyperGEN Study. BMC Med Genet 10:43PubMedCrossRefGoogle Scholar
  32. 32.
    Levy D, Neuhausen SL, Hunt SC, Kimura M, Hwang SJ, Chen W, Bis JC, Fitzpatrick AL, Smith E, Johnson AD et al (2010) Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci USA 107(20):9293–9298PubMedCrossRefGoogle Scholar
  33. 33.
    Prescott J, Kraft P, Chasman DI, Savage SA, Mirabello L, Berndt SI, Weissfeld JL, Han J, Hayes RB, Chanock SJ et al (2011) Genome-wide association study of relative telomere length. PLoS One 6(5):e19635PubMedCrossRefGoogle Scholar
  34. 34.
    Wong LS, de Boer RA, Samani NJ, van Veldhuisen DJ, van der Harst P (2008) Telomere biology in heart failure. Eur J Heart Fail 10(11):1049–1056PubMedCrossRefGoogle Scholar
  35. 35.
    Lang R, Bierig M, Devereux R, Flachskampf FA, Foster E, Pellikka P, Picard MH, Prather A, Roman MJ, Shanewise J et al (2006) Recommendations for chamber quantification. A report from the American Society of Echocardiography’s Nomenclature and Standards Committee, the Task Force on Chamber Quantification, and the European Association of Echocardiography. Eur J Echocardiogr 7(2):79–108PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Matthias Huber
    • 1
  • Andras Treszl
    • 2
  • Markus Wehland
    • 1
  • Ingke Winther
    • 1
  • Irina Zergibel
    • 1
  • Rona Reibis
    • 1
    • 3
  • Juliane Bolbrinker
    • 1
  • Monika Stoll
    • 4
  • Gilbert Schönfelder
    • 1
  • Karl Wegscheider
    • 2
  • Heinz Völler
    • 1
    • 3
  • Reinhold Kreutz
    • 1
  1. 1.Institute of Clinical Pharmacology and Toxicology, CharitéCentrum für TherapieforschungCharité–Universitätsmedizin BerlinBerlinGermany
  2. 2.Department of Medical Biometry and EpidemiologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Klinik am SeeRehabilitation Center for Cardiovascular DiseasesRüdersdorfGermany
  4. 4.Leibniz-Institute for Arteriosclerosis ResearchUniversity of MünsterMünsterGermany

Personalised recommendations