Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Gottardo, Lucia (2008) Studio di associazione tra varianti genetiche comuni nel loci dell' Interleukin-6 signal trasducer (IL6ST) e del recettore della leptina (LEPR) e alcuni marcatori di insulino resistenza e di infiammazione. [Tesi di dottorato]

Full text disponibile come:

[img]
Anteprima
Documento PDF
1233Kb

Abstract (inglese)

The term metabolic syndrome refers to the variable clustering of abdominal obesity, impaired glucose tolerance, dyslipidemia, and high blood pressure. Together, these metabolic abnormalities are associated with a greatly increased risk of type 2 diabetes mellitus and cardiovascular disease. Growing evidence suggests that a state of chronic low-grade inflammation may contribute to such clustering of metabolic abnormalities and to their association with diabetes and increased atherosclerosis. While the molecular mechanisms underlying the link between inflammation and metabolic syndrome are not known, many studies point to proinflammatory cytokines released by the adipose tissue as possible mediators. The aim of our study was to examine whether genetic variability at the genetic loci of some of these molecules and their receptors can modulate metabolic and inflammatory traits in non diabetics subjects. Here we show the results regarding the interleukin 6 signal transducer (IL6ST, also known as gp130) and leptin receptor (LEPR) genes, two receptors sharing partial sequencing homology and similar structure. We first established the LD structure at the IL6ST and LEPR loci to select htSNPs comprehensively capturing genetic variability at these loci then we evaluate whether genetic variants at IL6ST and LEPR loci can modulate metabolic and inflammatory traits in two healthy population, one from Padova (PD, n=630) the other from San Giovanni Rotondo (SGR, n=553).
The IL6ST study points to some genetic variants as possible determinants of impaired glucose metabolism and other abnormalities of the metabolic syndrome, while the LEPR study, by finding that variability in the gene is a significant predictor of CRP and fibrinogen levels, lends further support to the hypothesis that leptin has a physiological influence on inflammatory and prothrombotic traits.


Statistiche Download - Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Avogaro, Angelo
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > DIABETOLOGIA
Data di deposito della tesi:25 Gennaio 2008
Anno di Pubblicazione:25 Gennaio 2008
Parole chiave (italiano / inglese):polimorfismi genetica insulino-resistenza IL-6 leptina
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/13 Endocrinologia
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Clinica e Sperimentale
Codice ID:436
Depositato il:10 Ott 2008
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

1. Grundy SM, Brewer HB, Cleeman JI, et al. Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues related to definition. Circulation 2004; 109: 433-438. Cerca con Google

2. Alberti K, Zimmet P. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Report of WHO Consultation. Diabetic Med. 1998; 15: 539-553. Cerca con Google

3. Expert panel on detection, evaluation and treatment of high blood cholesterol in adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001; 285: 2486-2497. Cerca con Google

4. Lakka HM, Laaksonen DE, Lakka TA et al. The metabolic syndrome and total and cardiovascular disease mortality in middle aged men. JAMA. 2002; 288: 2709-2716. Cerca con Google

5. Dunaif A, Thomas A. Current concepts in the polycistic ovary syndrome. Annu Rev Med 2001; 52: 401-419. Cerca con Google

6. Marchesini G, Brizi M, Bianchi G, Tomasetti S, Bugianesi E Lenzi M et al. Non alcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 1844-53. Cerca con Google

7. Vuorinen-Markkola H, Yki-Jarvinen H. Hyperuricemia and insulin resistance. J Clin Endocrinol Metab. 1994; 78: 25-9. Cerca con Google

8. Aso Y, Wakabayashi S, Yamamoto R, et al. Metabolic syndrome accompanied by hypercholesterolemia is strongly associated with proinflammatory state and impairment of fibrinolysis in patients with type 2 diabetes: synergistic effects of plasminogen activator inhibitor-1 and thrombin-activatable fibrinolysis inhibitor. Diabetes Care. 2005;28(9):2211-6. Cerca con Google

9. Festa A, D’Agostino RJ, Howard G et al. Chronic subclinical inflammation as part of the insulin resistance sindrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102: 42-47. Cerca con Google

10. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome - a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006; 23(5):469-80. Cerca con Google

11. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006; 116(7):1793-801. Cerca con Google

12. Saltiel AR. You are what you secrete. Nat Med. 2001;7(8): 887-8. Cerca con Google

13. Scherer P. E. Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes. 2006; 55: 1537–1545. Cerca con Google

14. Wellen K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 2005; 115: 1111–1119. Cerca con Google

15. Yang Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005; 436, 356–362. Cerca con Google

16. Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes and the metabolic syndrome. J. Clin. Invest. 2006; 116: 1784–1792. Cerca con Google

17. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004; 145: 2273– 2282. Cerca con Google

18. Mooney RA et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J.Biol. Chem. 2001 276: 25889–25893. Cerca con Google

19. Perreault M, Marette A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nature Med. 2001; 7: 1138–1143. Cerca con Google

20. Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997; 46: 3–10. Cerca con Google

21. Roden M et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin.Invest. 1996; 97: 2859–2865. Cerca con Google

22. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004; 89(6): 2548-56. Cerca con Google

23. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006; 6(10): 772-83. Cerca con Google

24. Hida K. et al. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc. Natl Acad. Sci. 2005; 102, 10610–10615. Cerca con Google

25. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372:425-432. Cerca con Google

26. Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000; 62:413-437. Cerca con Google

27. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003; 111:1409-421. Cerca con Google

28. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987-997. Cerca con Google

29. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998; 394:897-901. Cerca con Google

30. Friedman J M, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998; 395, 763–770. Cerca con Google

31. Grunfeld C et al. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 1996; 97, 2152–2157. Cerca con Google

32. Sarraf, P et al. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med. 1997; 185, 171–175. Cerca con Google

33. La Cava A, Matarese G. The weight of leptin in immunity. Nature Rev Immunol. 2004; 4: 371-379. Cerca con Google

34. Konstantinides S, Schafer K, Koschnick S, Loskutoff DJ. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest. 2001; 108:1533-1540. Cerca con Google

35. Bodary PF, Westrick RJ, Wickenheiser KJ, Shen Y, Eitzman DT. Effect of leptin on arterial thrombosis following vascular injury in mice. JAMA. 2002; 287:1706-1709. Cerca con Google

36. Stephenson K, Tunstead J, Tsai A, Gordon R, Henderson S, Dansky HM. Neointimal formation after endovascular arterial injury is markedly attenuated in db/db mice. Arterioscler Thromb Vasc Biol. 2003; 23:2027-2033. Cerca con Google

37. Schafer K, Halle M, Goeschen C, Dellas C, Pynn M, Loskutoff DJ, Konstantinides S. Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol. 2004; 24:112-117. Cerca con Google

38. Shamsuzzaman AS, Winnicki M, Wolk R, Svatikova A, Phillips BG, Davison DE, Berger PB, Somers VK. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation. 2004; 109:2181-2185. Cerca con Google

39. Gomez-Ambrosi J, Salvador J, Paramo JA, Orbe J, de Irala J, Diez-Caballero A, Gil MJ, Cienfuegos JA, Fruhbeck G. Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors. Clin Biochem. 2002; 35:315-320. Cerca con Google

40. van Dielen FM, van't Veer C, Schols AM, Soeters PB, Buurman WA, Greve JW. Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. Int J Obes Relat Metab Disord. 2001; 25:1759-176, Cerca con Google

41. Reilly MP, Iqbal N, Schutta M, Wolfe ML, Scally M, Localio AR, Rader DJ, Kimmel SE. Plasma leptin levels are associated with coronary atherosclerosis in type 2 diabetes. J Clin Endocrinol Metab. 2004; 89:3872-3878. Cerca con Google

42. Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation. 2001; 104:3052-3056. Cerca con Google

43. Chu NF, Spiegelman D, Hotamisligil GS, Rifai N, Stampfer M, Rimm EB. Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men. Atherosclerosis. 2001; 157:495- 503. Cerca con Google

44. Hukshorn CJ, Lindeman JH, Toet KH, Saris WH, Eilers PH, Westerterp-Plantenga MS, Kooistra T. Leptin and the proinflammatory state associated with human obesity. J Clin Endocrinol Metab. 2004; 89:1773-1778. Cerca con Google

45. Chan JL, Bullen J, Stoyneva V, Depaoli AM, Addy C, Mantzoros CS. Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess. J Clin Endocrinol Metab. 2005; 90:1618-1624. Cerca con Google

46. Chan JL, Moschos SJ, Bullen J, Heist K, Li X, Kim YB, Kahn BB, Mantzoros CS. Recombinant methionyl human leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor-alpha receptor levels in humans with relative leptin deficiency. J Clin Endocrinol Metab. 2005; 90:1625-1631. Cerca con Google

47. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995; 83:1263-1271. Cerca con Google

48. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, Friedman JM. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci. USA. 1997; 94:7001-7005. Cerca con Google

49. Bjørbæk C, and Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog. Horm. Res. 2004; 59:305–331. Cerca con Google

50. Minokoshi Y, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004; 428:569–574. Cerca con Google

51. Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res. 2001; 9(7):414-7. Cerca con Google

52. Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol. 1997; 15:797-819. Cerca con Google

53. Wolford JK, Colligan PB, Gruber JD, Bogardus C. Variants in the interleukin 6 receptor gene are associated with obesity in Pima Indians. Mol Genet Metab. 2003; 80(3): 338- 343. Cerca con Google

54. Wang H, Zhang Z, Chu W, Cooper JJ, Elbein SC. Molecular screening and association analyses of the interleukin 6 receptor gene variants with type 2 diabetes, diabetic nephropathy, and insulin sensitivity. J Clin Endocrinol Metab. 2005; 90:1123–1129. Cerca con Google

55. Hamid YH, Urhammer SA, Jensen DP, et al. Variation in the interleukin-6 receptor gene associates with type 2 diabetes in Danish whites. Diabetes. 2004; 53:3342–3345. Cerca con Google

56. Esteve E, Villuendas G, Mallolas J, et al. Polymorphisms in the interleukin-6 receptor gene are associated with body mass index and with characteristics of the metabolic syndrome. Clin Endocrinol (Oxf). 2006; 65(1):88-91. Cerca con Google

57. Gabriel SB, Schaffnerv SF, Nguyen H, et al. The structure of haplotype blocks in the human genome. Science. 2002; 296:2225-2229. Cerca con Google

58. Abecasis GR, Cookson WO. GOLD - graphical overview of linkage disequilibrium. Bioinformatics. 2000; 16:182-183. Cerca con Google

59. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet. 2002; 70:425-434. Cerca con Google

60. Zhang K, Deng M, Chen T, Waterman MS, Sun FA: Dynamic programming algorithm for haplotype block partitioning. Proc Natl Acad Sci USA. 2002; 99:7335-7339. Cerca con Google

61. Varmus H. Genomic empowerment: the importance of public databases. Nat Genet 2003; 35 (suppl 1): 3. Cerca con Google

62. 17 Reich DE, Gabriel SB, Altshuler D. Quality and completeness of SNP databases. Nat Genet 2003; 33: 457–58. Cerca con Google

63. Carlson CS, Eberle MA, Kruglyak L, Nickerson DA. Mapping complex disease loci in whole-genome association studies. Nature 2004; 429: 446–52. Cerca con Google

64. Schork NJ, Fallin D, Lanchbury JS. Single nucleotide polymorphisms and the future of genetic epidemiology. Clin Genet 2000; 58: 250-264. Cerca con Google

65. Escobar-Morreale HF, Calvo RM, Villuendas G, Sancho J, San Millan JL. Association of polymorphisms in the interleukin 6 receptor complex with obesity and hyperandrogenism. Obes Res. 2003; 11(8):987-96. Cerca con Google

66. Luchtefeld M, Schunkert H, Stoll M et al. Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man. J Exp Med. 2007 Aug 6; 204(8):1935-44. Cerca con Google

67. Zhang YY, Gottardo L, Mlynarski et al. Genetic variability at the leptin receptor (LEPR) locus is a determinant of plasma fibrinogen and C-reactive protein levels. Atherosclerosis. 2007; 191(1):121-7. Cerca con Google

68. Ma X, Bacci S, Mlynarski W, et al. A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum Mol Genet. 2004; 13(19):2197-205. Cerca con Google

69. Lupo A. Nutrition in general practice in Italy. Am J Clin Nutr. 1997; 65(6 Suppl): 1963S-1966S. Cerca con Google

70. Correa Leite ML, Nicolosi A, Cristina S, Hauser WA, Pugliese P, Nappi G. Dietary and nutritional patterns in an elderly rural population in Northern and Southern Italy: (I). A cluster analysis of food consumption. Eur J Clin Nutr. 2003; 57(12):1514-21. Cerca con Google

71. Phillips C, Lopez-Miranda J, Perez-Jiminez F, McManus R, Roche HM. Genetic and nutrient determinants of the metabolic syndrome. Curr Opin Cardiol. 2006; 21:185–193. Cerca con Google

72. Senn JJ, Klover PJ, Nowak IA, et al. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem. 2003; 278(16): 13740-6. Cerca con Google

73. Ueki K, Kondo T, Tseng YH, Kahn CR. Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci U S A. 2004; 101(28):10422-7. Cerca con Google

74. Shamsuzzaman AS, Winnicki M, Wolk R, et al. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation 2004; 109: 2181–5. Cerca con Google

75. Chu NF, Spiegelman D, Hotamisligil GS, Rifai N, Stampfer M, Rimm EB. Plasma insulin, leptin, and soluble TNF receptors levels in relation to obesity-related atherogenic and thrombogenic cardiovascular disease risk factors among men. Atherosclerosis 2001; 157: 495– 503. Cerca con Google

76. Gomez-Ambrosi J, Salvador J, Paramo JA, et al. Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors. Clin Biochem 2002; 35: 315–20. Cerca con Google

77. Heo M, Leibel RL, Boyer BB, et al. Pooling analysis of genetic data: the association of leptin receptor (LEPR) polymorphisms with variables related to human adiposity. Genetics 2001; 159: 1163-78. Cerca con Google

78. Semenza GL. Transcription factors and human disease. New York, NY: Oxford University Press; 1998. Cerca con Google

79. Chan JL, Moschos SJ, Bullen J, et al. Recombinant methionyl human leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor-alpha receptor levels in humans with relative leptin deficiency. J Clin Endocrinol Metab 2005; 90: 1625–31. Cerca con Google

80. Wang Y, Kuropatwinski KK, White DW, et al. J Biol Chem 1997;272:16216–23. Cerca con Google

81. Hukshorn CJ, Lindeman JH, Toet KH, et al. Leptin and the proinflammatory state associated with human obesity. J Clin Endocrinol Metab 2004; 89: 1773–8. Cerca con Google

82. Chan JL, Bullen J, Stoyneva V, Depaoli AM, Addy C, Mantzoros CS. Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess. J Clin Endocrinol Metab 2005; 90: 1618–24. Cerca con Google

Download statistics

Solo per lo Staff dell Archivio: Modifica questo record

EPrints Logo
Padua@Research is powered by EPrints 3 which is developed by the School of Electronics and Computer Science at the University of Southampton. More information and software credits.