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Associations of insulin-like growth factor binding protein-3 gene polymorphisms with IGF-I activity and lipid parameters in adolescents

International Journal of Obesity volume 33, pages 1446–1453 (2009)Cite this article

Abstract

Objective:

Childhood obesity is a growing global epidemic. Recent studies indicate that obesity and related metabolic traits are highly heritable. Increasing evidence suggests that growth hormone (GH) and the insulin-like growth factor-I (IGF-I) axis have important functions in regulating adiposity and insulin sensitivity. Five single-nucleotide polymorphisms (SNPs) at IGF-binding protein-3 (IGFBP3) were genotyped to find their associations with IGF-1 activity level and common clinical metabolic traits.

Patients and Methods:

We examined the associations of five SNPs at IGFBP3 with serum IGF-I and IGFBP-3 levels, as well as with obesity-related metabolic traits in 981 Hong Kong Chinese adolescents. Factor analysis was used to reduce the intercorrelated variables to five factor scores indicating body composition, blood pressure, IGF-I activity, triglyceride (TG)+high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC)+low-density lipoprotein cholesterol (LDL-C) factor scores.

Results:

There was a strong association between the −202A/C polymorphism (rs2854744) and IGF-I activity (P=1.2 × 10−6) and TC+LDL-C factor scores (P=0.0085), corrected for age and sex. The C allele was associated with decreased IGFBP-3 levels (P=1.21 × 10−13), increased IGF-I/IGFBP-3 molar ratio (P=5.22 × 10−6) and decreased LDL-C (P=0.020). There was also a significant association between a G/A polymorphism at the 3′ flanking sequence (rs13223993) of the IGFBP3 gene and the TG+HDL-C factor score (P=0.0013). The minor A allele carriers of rs13223993 had a lower HDL-C (P=0.0067) level and a tendency toward a high TG level. Haplotype analysis did not increase the significance of associations between single SNPs and phenotypes.

Conclusion:

Our results support the function of IGFBP3 gene polymorphisms in modulating IGF-I activity and lipid levels in adolescents. Given the prognostic significance of IGF-I, IGFBPs and lipids on risk of diabetes, obesity and cancer, long-term studies are required to clarify the clinical meaning of these findings.

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References

  1. Daniels SR, Arnett DK, Eckel RH, Gidding SS, Hayman LL, Kumanyika S et al. Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment. Circulation 2005; 111: 1999–2012.

    Article  PubMed  Google Scholar 

  2. Ozaki R, Qiao Q, Wong GW, Chan MH, So WY, Tong PC et al. Overweight, family history of diabetes and attending schools of lower academic grading are independent predictors for metabolic syndrome in Hong Kong Chinese adolescents. Arch Dis Child 2007; 92: 224–228.

    Article  PubMed  Google Scholar 

  3. Steinberger J, Moran A, Hong CP, Jacobs Jr DR, Sinaiko AR . Adiposity in childhood predicts obesity and insulin resistance in young adulthood. J Pediatr 2001; 138: 469–473.

    Article  CAS  PubMed  Google Scholar 

  4. Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH . The disease burden associated with overweight and obesity. JAMA 1999; 282: 1523–1529.

    Article  CAS  PubMed  Google Scholar 

  5. Li JK, Ng MC, So WY, Chiu CK, Ozaki R, Tong PC et al. Phenotypic and genetic clustering of diabetes and metabolic syndrome in Chinese families with type 2 diabetes mellitus. Diabetes Metab Res Rev 2006; 22: 46–52.

    Article  CAS  PubMed  Google Scholar 

  6. Walley AJ, Blakemore AI, Froguel P . Genetics of obesity and the prediction of risk for health. Hum Mol Genet 2006; 15 (Spec No 2): R124–R130.

    Article  CAS  PubMed  Google Scholar 

  7. Lee ZS, Chan JC, Yeung VT, Chow CC, Lau MS, Ko GT et al. Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients. Diabetes Care 1999; 22: 1450–1457.

    Article  CAS  PubMed  Google Scholar 

  8. Tong PC, Ho CS, Yeung VT, Ng MC, So WY, Ozaki R et al. Association of testosterone, insulin-like growth factor-I, and C-reactive protein with metabolic syndrome in Chinese middle-aged men with a family history of type 2 diabetes. J Clin Endocrinol Metab 2005; 90: 6418–6423.

    Article  CAS  PubMed  Google Scholar 

  9. Nam SY, Kim KR, Cha BS, Song YD, Lim SK, Lee HC et al. Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients. Int J Obes Relat Metab Disord 2001; 25: 1101–1107.

    Article  CAS  PubMed  Google Scholar 

  10. Kong AP, Chan NN, Chan JC . The role of adipocytokines and neurohormonal dysregulation in metabolic syndrome. Curr Diabetes Rev 2006; 2: 397–407.

    Article  CAS  PubMed  Google Scholar 

  11. Veldhuis JD, Roemmich JN, Richmond EJ, Rogol AD, Lovejoy JC, Sheffield-Moore M et al. Endocrine control of body composition in infancy, childhood, and puberty. Endocr Rev 2005; 26: 114–146.

    Article  CAS  PubMed  Google Scholar 

  12. Le Roith D, Bondy C, Yakar S, Liu JL, Butler A . The somatomedin hypothesis: 2001. Endocr Rev 2001; 22: 53–74.

    Article  CAS  PubMed  Google Scholar 

  13. Baxter RC . Insulin-like growth factor binding proteins in the human circulation: a review. Horm Res 1994; 42: 140–144.

    Article  CAS  PubMed  Google Scholar 

  14. Jones JI, Clemmons DR . Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16: 3–34.

    CAS  PubMed  Google Scholar 

  15. Wallander M, Norhammar A, Malmberg K, Ohrvik J, Ryden L, Brismar K . IGF binding protein 1 predicts cardiovascular morbidity and mortality in patients with acute myocardial infarction and type 2 diabetes. Diabetes Care 2007; 30: 2343–2348.

    Article  CAS  PubMed  Google Scholar 

  16. Wheatcroft SB, Kearney MT, Shah AM, Ezzat VA, Miell JR, Modo M et al. IGF-binding protein-2 protects against the development of obesity and insulin resistance. Diabetes 2007; 56: 285–294.

    Article  CAS  PubMed  Google Scholar 

  17. Saydah S, Graubard B, Ballard-Barbash R, Berrigan D . Insulin-like growth factors and subsequent risk of mortality in the United States. Am J Epidemiol 2007; 166: 518–526.

    Article  PubMed  Google Scholar 

  18. Mauras N, Blizzard RM, Link K, Johnson ML, Rogol AD, Veldhuis JD . Augmentation of growth hormone secretion during puberty: evidence for a pulse amplitude-modulated phenomenon. J Clin Endocrinol Metab 1987; 64: 596–601.

    Article  CAS  PubMed  Google Scholar 

  19. Ng VW, Kong AP, Choi KC, Ozaki R, Wong GW, So WY et al. BMI and waist circumference in predicting cardiovascular risk factor clustering in Chinese adolescents. Obesity (Silver Spring) 2007; 15: 494–503.

    Article  Google Scholar 

  20. Kong AP, Wong GW, Choi KC, Ho CS, Chan MH, Lam CW et al. Reference values for serum levels of insulin-like growth factor (IGF-1) and IGF-binding protein 3 (IGFBP-3) and their ratio in Chinese adolescents. Clin Biochem 2007; 40: 1093–1099.

    Article  CAS  PubMed  Google Scholar 

  21. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  PubMed  Google Scholar 

  22. Purcell S, Cherny SS, Sham PC . Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.

    Article  CAS  PubMed  Google Scholar 

  23. Fletcher O, Gibson L, Johnson N, Altmann DR, Holly JM, Ashworth A et al. Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review. Cancer Epidemiol Biomarkers Prev 2005; 14: 2–19.

    CAS  PubMed  Google Scholar 

  24. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 2003; 63: 8912–8921.

    CAS  PubMed  Google Scholar 

  26. Sachdev D, Li SL, Hartell JS, Fujita-Yamaguchi Y, Miller JS, Yee D . A chimeric humanized single-chain antibody against the type I insulin-like growth factor (IGF) receptor renders breast cancer cells refractory to the mitogenic effects of IGF-I. Cancer Res 2003; 63: 627–635.

    CAS  PubMed  Google Scholar 

  27. Renehan AG, Zwahlen M, Minder C, O′Dwyer ST, Shalet SM, Egger M . Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 2004; 363: 1346–1353.

    Article  CAS  PubMed  Google Scholar 

  28. Hochberg Z, Hertz P, Maor G, Oiknine J, Aviram M . Growth hormone and insulin-like growth factor-I increase macrophage uptake and degradation of low density lipoprotein. Endocrinology 1992; 131: 430–435.

    Article  CAS  PubMed  Google Scholar 

  29. Ottosson M, Vikman-Adolfsson K, Enerback S, Elander A, Bjorntorp P, Eden S . Growth hormone inhibits lipoprotein lipase activity in human adipose tissue. J Clin Endocrinol Metab 1995; 80: 936–941.

    CAS  PubMed  Google Scholar 

  30. Yang X, So WY, Ko GT, Ma RC, Kong AP, Chow CC et al. Independent associations between low-density lipoprotein cholesterol and cancer among patients with type 2 diabetes mellitus. CMAJ 2008; 179: 427–437.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Paquette J, Bessette B, Ledru E, Deal C . Identification of upstream stimulatory factor binding sites in the human IGFBP3 promoter and potential implication of adjacent single-nucleotide polymorphisms and responsiveness to insulin. Endocrinology 2007; 148: 6007–6018.

    Article  CAS  PubMed  Google Scholar 

  32. Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M et al. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet 2004; 36: 371–376.

    Article  CAS  PubMed  Google Scholar 

  33. Ng MC, Miyake K, So WY, Poon EW, Lam VK, Li JK et al. The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population. Diabetologia 2005; 48: 2018–2024.

    Article  CAS  PubMed  Google Scholar 

  34. Lee PD, Giudice LC, Conover CA, Powell DR . Insulin-like growth factor binding protein-1: recent findings and new directions. Proc Soc Exp Biol Med 1997; 216: 319–357.

    Article  CAS  PubMed  Google Scholar 

  35. Conover CA, Lee PD, Kanaley JA, Clarkson JT, Jensen MD . Insulin regulation of insulin-like growth factor binding protein-1 in obese and nonobese humans. J Clin Endocrinol Metab 1992; 74: 1355–1360.

    CAS  PubMed  Google Scholar 

  36. Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK et al. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 1997; 21: 355–359.

    Article  CAS  PubMed  Google Scholar 

  37. Heald AH, Cruickshank JK, Riste LK, Cade JE, Anderson S, Greenhalgh A et al. Close relation of fasting insulin-like growth factor binding protein-1 (IGFBP-1) with glucose tolerance and cardiovascular risk in two populations. Diabetologia 2001; 44: 333–339.

    Article  CAS  PubMed  Google Scholar 

  38. Heald AH, Siddals KW, Fraser W, Taylor W, Kaushal K, Morris J et al. Low circulating levels of insulin-like growth factor binding protein-1 (IGFBP-1) are closely associated with the presence of macrovascular disease and hypertension in type 2 diabetes. Diabetes 2002; 51: 2629–2636.

    Article  CAS  PubMed  Google Scholar 

  39. Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T . Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 2002; 106: 939–944.

    Article  CAS  PubMed  Google Scholar 

  40. Laughlin GA, Barrett-Connor E, Criqui MH, Kritz-Silverstein D . The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo Study. J Clin Endocrinol Metab 2004; 89: 114–120.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Croucher Foundation and the Research Grants Council of the Hong Kong Special Administrative Region, China (CUHK 4055/01M).

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Authors and Affiliations

  1. Department of Biochemistry, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China

    J L Y Mong, G S Guldan & M M Y Waye

  2. Croucher Laboratory for Human Genomics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China

    J L Y Mong & M M Y Waye

  3. Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China

    M C Y Ng, C H T Tam, H M Lee, R C W Ma, W Y So, A P S Kong & J C N Chan

  4. Department of Paediatrics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China

    G W K Wong

  5. Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China

    A P S Kong & J C N Chan

  6. Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong SAR, China

    J C N Chan

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  1. J L Y Mong
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Correspondence to J C N Chan.

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Mong, J., Ng, M., Guldan, G. et al. Associations of insulin-like growth factor binding protein-3 gene polymorphisms with IGF-I activity and lipid parameters in adolescents. Int J Obes 33, 1446–1453 (2009). https://doi.org/10.1038/ijo.2009.186

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