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Does Apolipoprotein E genotype affect cardiovascular risk in subjects with acromegaly?

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Abstract

Acromegaly is a syndrome that results when the pituitary gland produces excess growth hormone after epiphyseal closure at puberty. Usually, subjects with acromegaly exhibit a 2- to 3-fold higher mortality rate from diseases that are associated with cardiovascular complications when compared to the normal population. In this study, we therefore aimed to evaluate whether a well-established cardiovascular risk factor, the Apolipoprotein E (Apo E) genotype, contributes to increased risk of cardiovascular complications in subjects with acromegaly. A total of 102 unrelated acromegaly subjects were prospectively included into this case–control association study and constituted our study group. The study group was comparable by age and gender with 200 unrelated healthy subjects constituting our control group. Genomic DNA was isolated from the peripheral blood leukocytes of all subjects and Apo E genotype (codon 112/158) was assessed by melting temperature analyses after using a real-time PCR protocol. The Apolipoprotein E4 allele was found at a significantly higher frequency in the study group when compared with the control group (P = 0.032). Subjects with the E2 allele, on the other hand, had significantly increased values in body mass index (P = 0.004), waist circumference (P = 0.001), C-reactive protein (CRP) (P < 0.001), and left-side carotid intima media thickness (P = 0.025). The Apolipoprotein E2 genotype might contribute to increased risk of cardiovascular complications in subjects with acromegaly since it is concurrently present with other cardiovascular risk factors such as the left-side carotid intima media thickness and CRP.

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Abbreviations

Apo E:

Apolipoprotein E

BMI:

Body mass index

CIMT:

Carotid intima-media thickness

CRP:

C-reactive protein

CVD:

Cardiovascular disease

EDTA:

Ethylenediaminetetraacetic acid

FMD:

Flow-mediated dilation

GH:

Growth hormone

HDL:

High density lipoprotein

IDL:

Intermediate density lipoprotein

IGF-1:

Insulin-like growth factor-1

LDL:

Low density lipoprotein

OGTT:

Oral glucose tolerance test

US:

Ultrasound

VLDL:

Very low density lipoprotein

References

  1. P. Chanson, S. Salenave, P. Kamenicky, L. Cazabat, J. Young, Pituitary tumours: acromegaly. Best Pract. Res. 23(5), 555–574 (2009)

    Article  CAS  Google Scholar 

  2. A. Colao, G. Vitale, R. Pivonello, A. Ciccarelli, C. Di Somma, G. Lombardi, The heart: an end-organ of GH action. Eur. J. Endocrinol./Eur. Fed. Endocr. Soc. 151(Suppl. 1), S93–S101 (2004)

    Article  CAS  Google Scholar 

  3. R.W. Mahley, K.E. Palaoglu, Z. Atak, J. Dawson-Pepin, A.M. Langlois, V. Cheung, H. Onat, P. Fulks, L.L. Mahley, F. Vakar et al., Turkish Heart Study: lipids, lipoproteins, and apolipoproteins. J. Lipid Res. 36(4), 839–859 (1995)

    PubMed  CAS  Google Scholar 

  4. T.L. Innerarity, E.J. Friedlander, S.C. Rall Jr., K.H. Weisgraber, R.W. Mahley, The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments. J. Biol. Chem. 258(20), 12341–12347 (1983)

    PubMed  CAS  Google Scholar 

  5. Y.A. Kesaniemi, C. Ehnholm, T.A. Miettinen, Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype. J. Clin. Investig. 80(2), 578–581 (1987)

    Article  PubMed  CAS  Google Scholar 

  6. J. Wildbrett, M. Hanefeld, K. Fucker, T. Pinzer, S. Bergmann, G. Siegert, M. Breidert, Anomalies of lipoprotein pattern and fibrinolysis in acromegalic patients: relation to growth hormone levels and insulin-like growth factor I. Exp. Clin. Endocrinol. Diabetes 105(6), 331–335 (1997)

    Article  PubMed  CAS  Google Scholar 

  7. C. Rocken, D. Paris, K. Steusloff, W. Saeger, Investigation of the presence of apotipoprotein E, G lycosaminoglycans, basement membrane proteins, and protease inhibitors in senile interstitial amyloid of the pituitary. Endocr. Pathol. 8(3), 205–214 (1997)

    Article  PubMed  CAS  Google Scholar 

  8. K. Steusloff, C. Rocken, W. Saeger, Basement membrane proteins, apolipoprotein E and glycosaminoglycans in pituitary adenomas and their correlation to amyloid. Virchows Arch. 433(1), 29–34 (1998)

    Article  PubMed  CAS  Google Scholar 

  9. A. Giustina, P. Chanson, M.D. Bronstein, A. Klibanski, S. Lamberts, F.F. Casanueva, P. Trainer, E. Ghigo, K. Ho, S. Melmed, A consensus on criteria for cure of acromegaly. J. Clin. Endocrinol. Metab. 95(7), 3141–3148 (2010)

    Article  PubMed  CAS  Google Scholar 

  10. F.H. Ebner, V. Kuerschner, K. Dietz, E. Bueltmann, T. Naegele, J. Honegger, Reduced intercarotid artery distance in acromegaly: pathophysiologic considerations and implications for transsphenoidal surgery. Surg. Neurol. 72(5), 456–460 (2009). discussion 460

    Article  PubMed  Google Scholar 

  11. H. Ward, P.N. Mitrou, R. Bowman, R. Luben, N.J. Wareham, K.T. Khaw, S. Bingham, APOE genotype, lipids, and coronary heart disease risk: a prospective population study. Arch. Intern. Med. 169(15), 1424–1429 (2009)

    Article  PubMed  Google Scholar 

  12. A. Colao, D. Ferone, P. Marzullo, G. Lombardi, Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr. Rev. 25(1), 102–152 (2004)

    Article  PubMed  CAS  Google Scholar 

  13. T. Nieminen, M. Kahonen, L.E. Viiri, P. Gronroos, T. Lehtimaki, Pharmacogenetics of apolipoprotein E gene during lipid-lowering therapy: lipid levels and prevention of coronary heart disease. Pharmacogenomics 9(10), 1475–1486 (2008)

    Article  PubMed  CAS  Google Scholar 

  14. J.E. Eichner, S.T. Dunn, G. Perveen, D.M. Thompson, K.E. Stewart, B.C. Stroehla, Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am. J. Epidemiol. 155(6), 487–495 (2002)

    Article  PubMed  Google Scholar 

  15. W. Niu, Y. Qi, Y. Qian, P. Gao, D. Zhu, The relationship between apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphisms and hypertension: a meta-analysis of six studies comprising 1812 cases and 1762 controls. Hypertens. Res. 32(12), 1060–1066 (2009)

    Article  PubMed  CAS  Google Scholar 

  16. S. Heide, K. Manfred, C. Glaser, S. Schulz, Apolipoprotein E (apoE) polymorphism: a risk factor for fatal coronary sclerosis? Forensic Sci. Int. 192(1–3), 62–66 (2009)

    Article  PubMed  CAS  Google Scholar 

  17. P. Georgoulias, G. Wozniak, M. Samara, I. Chiotoglou, A. Kontos, C. Tzavara, V. Valotassiou, M. Georgitsi, V. Aleporou-Marinou, G.P. Patrinos, P. Kollia, Impact of ACE and ApoE polymorphisms on myocardial perfusion: correlation with myocardial single photon emission computed tomographic imaging. J. Hum. Genet. 54(10), 595–602 (2009)

    Article  PubMed  CAS  Google Scholar 

  18. R. Yang, L. Powell-Braxton, A.K. Ogaoawara, N. Dybdal, S. Bunting, O. Ohneda, H. Jin, Hypertension and endothelial dysfunction in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 19(11), 2762–2768 (1999)

    Article  PubMed  CAS  Google Scholar 

  19. E.S. Ford, Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 28(7), 1769–1778 (2005)

    Article  PubMed  Google Scholar 

  20. H.M. Zeljko, T. Skaric-Juric, N.S. Narancic, Z. Tomas, A. Baresic, M.P. Salihovic, B. Starcevic, B. Janicijevic, E2 allele of the Apolipoprotein E gene polymorphism is predictive for obesity status in Roma minority population of Croatia. Lipids Health Dis. 10(1), 9 (2011)

    Article  PubMed  CAS  Google Scholar 

  21. T. Yamamura, S. Tajima, Y. Miyake, S. Nomura, A. Yamamoto, K. Haze, K. Hiramori, Hyperlipoproteinemia as a risk factor for ischemic heart disease. Jpn. Circ. J. 54(4), 448–456 (1990)

    Article  PubMed  CAS  Google Scholar 

  22. P.W. Wilson, E.J. Schaefer, M.G. Larson, J.M. Ordovas, Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler. Thromb. Vasc. Biol. 16(10), 1250–1255 (1996)

    Article  PubMed  CAS  Google Scholar 

  23. M. Kaluzny, M. Bolanowski, J. Daroszewski, A. Szuba, The role of fibrinogen and CRP in cardiovascular risk in patients with acromegaly. Endokrynol. Pol. 61(1), 83–88 (2010)

    PubMed  CAS  Google Scholar 

  24. J.A. Hubacek, A. Peasey, H. Pikhart, P. Stavek, R. Kubinova, M. Marmot, M. Bobak, APOE polymorphism and its effect on plasma C-reactive protein levels in a large general population sample. Hum. Immunol. 71(3), 304–308 (2010)

    Article  PubMed  CAS  Google Scholar 

  25. R. Judson, C. Brain, B. Dain, A. Windemuth, G. Ruano, C. Reed, New and confirmatory evidence of an association between APOE genotype and baseline C-reactive protein in dyslipidemic individuals. Atherosclerosis 177(2), 345–351 (2004)

    Article  PubMed  CAS  Google Scholar 

  26. P. Gronroos, O.T. Raitakari, M. Kahonen, N. Hutri-Kahonen, J. Marniemi, J. Viikari, T. Lehtimaki, Association of high sensitive C-reactive protein with apolipoprotein E polymorphism in children and young adults: the Cardiovascular Risk in Young Finns Study. Clin. Chem. Lab. Med. 46(2), 179–186 (2008)

    Article  PubMed  CAS  Google Scholar 

  27. R. Rontu, P. Ojala, A. Hervonen, S. Goebeler, P.J. Karhunen, M. Nikkila, T. Kunnas, M. Jylha, C. Eklund, M. Hurme, T. Lehtimaki, Apolipoprotein E genotype is related to plasma levels of C-reactive protein and lipids and to longevity in nonagenarians. Clin. Endocrinol. 64(3), 265–270 (2006)

    Article  CAS  Google Scholar 

  28. A. Agrawal, D.J. Hammond Jr., S.K. Singh, Atherosclerosis-related functions of C-reactive protein. Cardiovasc. Hematol. Disord. Drug Targ. 10(4), 235–240 (2010)

    CAS  Google Scholar 

  29. Y. Song, M.J. Stampfer, S. Liu, Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann. Intern. Med. 141(2), 137–147 (2004)

    PubMed  Google Scholar 

  30. J. Kahri, A. Soro-Paavonen, C. Ehnholm, M.R. Taskinen, ApoE polymorphism is associated with C-reactive protein in low-HDL family members and in normolipidemic subjects. Mediators Inflamm. 2006(3), 12587 (2006)

    PubMed  Google Scholar 

  31. W. Marz, H. Scharnagl, M.M. Hoffmann, B.O. Boehm, B.R. Winkelmann, The apolipoprotein E polymorphism is associated with circulating C-reactive protein (the Ludwigshafen risk and cardiovascular health study). Eur. Heart J. 25(23), 2109–2119 (2004)

    Article  PubMed  Google Scholar 

  32. P. Delafontaine, Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc. Res. 30(6), 825–834 (1995)

    PubMed  CAS  Google Scholar 

  33. A. Cittadini, Y. Ishiguro, H. Stromer, M. Spindler, A.C. Moses, R. Clark, P.S. Douglas, J.S. Ingwall, J.P. Morgan, Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated muscles. Circ. Res. 83(1), 50–59 (1998)

    PubMed  CAS  Google Scholar 

  34. R.N. Clayton, Cardiovascular function in acromegaly. Endocr. Rev. 24(3), 272–277 (2003)

    Article  PubMed  CAS  Google Scholar 

  35. A. Colao, 5 Long-term acromegaly and associated cardiovascular complications: a case-based review. Best Pract. Res. 23(Suppl 1), S31–S38 (2009)

    Article  Google Scholar 

  36. A. Kablak-Ziembicka, T. Przewlocki, A. Sokolowski, W. Tracz, P. Podolec, Carotid intima-media thickness, hs-CRP and TNF-alpha are independently associated with cardiovascular event risk in patients with atherosclerotic occlusive disease. Atherosclerosis 214(1), 185–190 (2011)

    Article  PubMed  CAS  Google Scholar 

  37. H. Ozkan, O. Celik, E. Hatipoglu, F. Kantarci, P. Kadioglu, Procalcitonin can be used as a marker of premature atherosclerosis in acromegaly. Pituitary (2011). doi:10.1007/s11102-011-0327-y

  38. A.N. Paisley, M. Banerjee, M. Rezai, R.E. Schofield, S. Balakrishnannair, A. Herbert, J.A. Lawrance, P.J. Trainer, J.K. Cruickshank, Changes in arterial stiffness but not carotid intimal thickness in acromegaly. J. Clin. Endocrinol. Metab. 96(5), 1486–1492 (2011)

    Article  PubMed  CAS  Google Scholar 

  39. M. Otsuki, S. Kasayama, H. Yamamoto, H. Saito, S. Sumitani, H. Kouhara, Y. Saitoh, T. Ohnishi, N. Arita, Characterization of premature atherosclerosis of carotid arteries in acromegalic patients. Clin. Endocrinol. 54(6), 791–796 (2001)

    Article  CAS  Google Scholar 

  40. L. Paternoster, N.A. Martinez Gonzalez, S. Lewis, C. Sudlow, Association between apolipoprotein E genotype and carotid intima-media thickness may suggest a specific effect on large artery atherothrombotic stroke. Stroke 39(1), 48–54 (2008)

    Article  PubMed  Google Scholar 

  41. I.J. Andersson, A. Ljungberg, L. Svensson, L.M. Gan, J. Oscarsson, G. Bergstrom, Increased atherosclerotic lesion area in apoE deficient mice overexpressing bovine growth hormone. Atherosclerosis 188(2), 331–340 (2006)

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Biology, Ege University Medical School, 35100, Bornova, Izmir, Turkey

    Vildan Bozok Cetintas, Asli Tetik, Ali Sahin Kucukaslan, Buket Kosova & Zuhal Eroglu

  2. Division of Internal Medicine, Department of Endocrinology and Metabolic Disease, Ege University Medical School, Izmir, Turkey

    Ayhan Zengi, Serap Baydur Sahin & Fusun Saygılı

  3. Department of Radio Diagnostic, Ege University Medical School, Izmir, Turkey

    Sadik Tamsel

  4. Department of Endocrinology, Health Application and Research Center, Sifa University, Izmir, Turkey

    Muammer Karadeniz

  5. Department of Endocrinology and Metabolic Disease, Tepecik Training and Research Hospital, Izmir, Turkey

    Faruk Ergonen

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  1. Vildan Bozok Cetintas
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Bozok Cetintas, V., Zengi, A., Tetik, A. et al. Does Apolipoprotein E genotype affect cardiovascular risk in subjects with acromegaly?. Endocrine 41, 465–472 (2012). https://doi.org/10.1007/s12020-011-9585-8

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